Vipul Sheth, MD, PhD

All Publications

• MR-guided focused ultrasound therapy of extra-abdominal desmoid tumors: a multicenter retrospective study of 105 patients. European radiology Düx, D. M., Baal, J. D., Bitton, R., Chen, J., Brunsing, R. L., Sheth, V. R., Rosenberg, J., Kim, K., Ozhinsky, E., Avedian, R., Ganjoo, K., Bucknor, M., Dobrotwir, A., Ghanouni, P. 2023

  Abstract

  To assess the safety and efficacy of magnetic resonance-guided focused ultrasound (MRgFUS) for the treatment extra-abdominal desmoids.A total of 105 patients with desmoid fibromatosis (79 females, 26 males; 35 ± 14 years) were treated with MRgFUS between 2011 and 2021 in three centers. Total and viable tumors were evaluated per patient at last follow-up after treatment. Response and progression-free survival (PFS) were assessed with (modified) response evaluation criteria in solid tumors (RECIST v.1.1 and mRECIST). Change in Numerical Rating Scale (NRS) pain and 36-item Short Form Health Survey (SF-36) scores were compared. Treatment-related adverse events were recorded.The median initial tumor volume was 114 mL (IQR 314 mL). After MRgFUS, median total and viable tumor volume decreased to 51 mL (95% CI: 30-71 mL, n = 101, p < 0.0001) and 29 mL (95% CI: 17-57 mL, n = 88, p < 0.0001), respectively, at last follow-up (median: 15 months, 95% CI: 11-20 months). Based on total tumor measurements (RECIST), 86% (95% CI: 75-93%) had at least stable disease or better at last follow-up, but 50% (95% CI: 38-62%) of remaining viable nodules (mRECIST) progressed within the tumor. Median PFS was reached at 17 and 13 months for total and viable tumors, respectively. NRS decreased from 6 (IQR 3) to 3 (IQR 4) (p < 0.001). SF-36 scores improved (physical health (41 (IQR 15) to 46 (IQR 12); p = 0.05, and mental health (49 (IQR 17) to 53 (IQR 9); p = 0.02)). Complications occurred in 36%, most commonly 1st/2nd degree skin burns.MRgFUS reduced tumor volume, reduced pain, and improved quality of life in this series of 105 patients with extra-abdominal desmoid fibromatosis.Imaging-guided ablation is being increasingly used as an alternative to surgery, radiation, and medical therapy for the treatment of desmoid fibromatosis. MR-guided high-intensity focused ultrasound is an incisionless ablation technique that can be used to reduce tumor burden effectively and safely.• Desmoid fibromatosis was treated with MR-guided high-intensity focused ultrasound in 105 patients. • MR-guided focused ultrasound ablation reduced tumor volume and pain and improved quality of life. • MR-guided focused ultrasound is a treatment option for patients with extra-abdominal desmoid tumors.

  View details for DOI 10.1007/s00330-023-10073-9

  View details for PubMedID 37615768

• Predicting treatment response for the safe non-operative management of patients with rectal cancer using an MRI-based deep-learning model Selby, H. M., Liu, C., Sheth, V., Napel, S., Wagner, T., Morris, A. M. LIPPINCOTT WILLIAMS & WILKINS. 2023

  View details for Web of Science ID 001053772002055

• Sarcopenia Is a Risk Factor for Pelvic Organ Prolapse Independent of Age Sheth, V., Becker, L., Liang, T., Gurland, B., Neshatian, L. LIPPINCOTT WILLIAMS & WILKINS. 2021: S243

  View details for Web of Science ID 000717526101012

• Consensus Definitions and Interpretation Templates for Magnetic Resonance Imaging of Defecatory Pelvic Floor Disorders: Proceedings of the Consensus Meeting of the Pelvic Floor Disorders Consortium of the American Society of Colon and Rectal Surgeons, the Society of Abdominal Radiology, the International Continence Society, the American Urogynecologic Society, the International Urogynecological Association, and the Society of Gynecologic Surgeons. AJR. American journal of roentgenology Gurland, B. H., Khatri, G., Ram, R., Hull, T. L., Kocjancic, E., Quiroz, L. H., Sayed, R. F., Jambhekar, K. R., Chernyak, V., Paspulati, R. M., Sheth, V. R., Steiner, A. M., Kamath, A., Shobeiri, S. A., Weinstein, M. M., Bordeianou, L., Members of the Expert Workgroup on Magnetic Resonance Imaging of Pelvic Floor Disorders, Ayscue, J., Basilio, P., Chernyak, V., El Sayed, R. F., Gurland, B., Hall, C., Herrmann, K., Jambhekar, K., Kaiser, A. M., Kamath, A., Khatri, G., Kocjancic, E., Rafatzand, K., Rodriguez, L. M., Mishra, K., Neshatian, L., O'Neill, E., Parlade, A., Paspulati, R. M., Ram, R., Sheth, V., Steiner, A., Syan, R., Traugott, A. 2021: 1-13

  Abstract

  The Pelvic Floor Disorders Consortium (PFDC) is a multidisciplinary organization of colorectal surgeons, urogynecologists, urologists, gynecologists, gastroenterologists, radiologists, physiotherapists, and other advanced care practitioners. Specialists from these fields are all dedicated to the diagnosis and management of patients with pelvic floor conditions, but they approach, evaluate, and treat such patients with their own unique perspectives given the differences in their respective training. The PFDC was formed to bridge gaps and enable collaboration between these specialties. The goal of the PFDC is to develop and evaluate educational programs, create clinical guidelines and algorithms, and promote high quality of care in this unique patient population. The recommendations included in this article represent the work of the PFDC Working Group on Magnetic Resonance Imaging of Pelvic Floor Disorders (members listed alphabetically in Table 1). The objective was to generate inclusive, rather than prescriptive, guidance for all practitioners, irrespective of discipline, involved in the evaluation and treatment of patients with pelvic floor disorders.

  View details for DOI 10.2214/AJR.21.26488

  View details for PubMedID 34505543

• Nonoperative Management for Rectal Cancer. Cancer journal (Sudbury, Mass.) Pollom, E. L., Sheth, V. R., Dawes, A. J., Holden, T. 2024; 30 (4): 238-244

  Abstract

  The treatment paradigm for rectal cancer has been shifting toward de-escalated approaches to preserve patient quality of life. Historically, the standard treatment in the United States for locally advanced rectal cancer has standardly comprised preoperative chemoradiotherapy coupled with total mesorectal excision. Recent data challenge this "one-size-fits-all" strategy, supporting the possibility of omitting surgery for certain patients who achieve a clinical complete response to neoadjuvant therapy. Consequently, patients and their physicians must navigate diverse neoadjuvant options, often in the context of pursuing organ preservation. Total neoadjuvant therapy, involving the administration of all chemotherapy and radiation before total mesorectal excision, is associated with the highest rates of clinical complete response. However, questions persist regarding the optimal sequencing of radiation and chemotherapy and the choice between short-course and long-course radiation. Additionally, meticulous response assessment and surveillance are critical for selecting patients for nonoperative management without compromising the excellent cure rates associated with trimodality therapy. As nonoperative management becomes increasingly recognized as a standard-of-care treatment option for patients with rectal cancer, ongoing research in patient selection and monitoring as well as patient-reported outcomes is critical to guide personalized rectal cancer management within a patient-centered framework.

  View details for DOI 10.1097/PPO.0000000000000727

  View details for PubMedID 39042774

• Parametric response mapping of co-registered intravoxel incoherent motion magnetic resonance imaging and positron emission tomography in locally advanced cervical cancer undergoing concurrent chemoradiation therapy. Physics and imaging in radiation oncology Capaldi, D. P., Wang, J. Y., Liu, L., Sheth, V. R., Kidd, E. A., Hristov, D. H. 2024; 31: 100630

  Abstract

  Intravoxel-incoherent-motion (IVIM) magnetic-resonance-imaging (MRI) and positron-emission-tomography (PET) have been investigated independently but not voxel-wise to evaluate tumor microenvironment in cervical carcinoma patients. Whether regionally combined information of IVIM and PET offers additional predictive benefit over each modality independently has not been explored. Here, we investigated parametric-response-mapping (PRM) of co-registered PET and IVIM in cervical cancer patients to identify sub-volumes that may predict tumor shrinkage to concurrent-chemoradiation-therapy (CCRT).Twenty cervical cancer patients (age: 63[41-85]) were retrospectively evaluated. Diffusion-weighted-images (DWIs) were acquired on 3.0 T MRIs using a free-breathing single-shot-spin echo-planar-imaging (EPI) sequence. Pre- and on-treatment (∼after four-weeks of CCRT) MRI and pre-treatment FDG-PET/CT were acquired. IVIM model-fitting on the DWIs was performed using a Bayesian-fitting simplified two-compartment model. Three-dimensional rigidly-registered maps of PET/CT standardized-uptake-value (SUV) and IVIM diffusion-coefficient (D) and perfusion-fraction (f) were generated. Population-means of PET-SUV, IVIM-D and IVIM-f from pre-treatment-scans were calculated and used to generate PRM via a voxel-wise joint-histogram-analysis to classify voxels as high/low metabolic-activity and with high/low (hi/lo) cellular-density. Similar PRM maps were generated for SUV and f.Tumor-volume (p < 0.001) significantly decreased, while IVIM-f (p = 0.002) and IVIM-D (p = 0.03) significantly increased on-treatment. Pre-treatment tumor-volume (r = -0.45,p = 0.04) and PRM-SUVhi D lo (r = -0.65,p = 0.002) negatively correlated with ΔGTV, while pre-treatment IVIM-D (r = 0.64,p = 0.002), PRM-SUVlo f hi (r = 0.52,p = 0.02), and PRM-SUVlo D hi (r = 0.74,p < 0.001) positively correlated with ΔGTV.IVIM and PET was performed on cervical cancer patients undergoing CCRT and we observed that both IVIM-f and IVIM-D increased during treatment. Additionally, PRM was applied, and sub-volumes were identified that were related to ΔGTV.

  View details for DOI 10.1016/j.phro.2024.100630

  View details for PubMedID 39262680

  View details for PubMedCentralID PMC11387531

• Phase II trial of organ preservation program using short-course radiation and FOLFOXIRI for rectal cancer (SHORT-FOX). Pollom, E. L., Fisher, G. A., Shelton, A., Johnson, T., Chen, C., Jackson, S., Shaheen, S., Holden, T., Bien, J., King, D., Morris, A. M., Kin, C., Dawes, A., Kirilcuk, N., Gahagan, J., Vitzthum, L., Sheth, V., Brown, E., Pratapneni, A., Chang, D. LIPPINCOTT WILLIAMS & WILKINS. 2024

  View details for Web of Science ID 001275557400852

• Application of PET/MRI in Gynecologic Malignancies. Cancers Ebrahimi, S., Lundstrom, E., Batasin, S. J., Hedlund, E., Stalberg, K., Ehman, E. C., Sheth, V. R., Iranpour, N., Loubrie, S., Schlein, A., Rakow-Penner, R. 2024; 16 (8)

  Abstract

  The diagnosis, treatment, and management of gynecologic malignancies benefit from both positron emission tomography/computed tomography (PET/CT) and MRI. PET/CT provides important information on the local extent of disease as well as diffuse metastatic involvement. MRI offers soft tissue delineation and loco-regional disease involvement. The combination of these two technologies is key in diagnosis, treatment planning, and evaluating treatment response in gynecological malignancies. This review aims to assess the performance of PET/MRI in gynecologic cancer patients and outlines the technical challenges and clinical advantages of PET/MR systems when specifically applied to gynecologic malignancies.

  View details for DOI 10.3390/cancers16081478

  View details for PubMedID 38672560

• Use of a footstool improves rectal balloon expulsion in some patients with defecatory disorders. Neurogastroenterology and motility Ulsh, L., Halawi, H., Triadafilopoulos, G., Gurland, B., Nguyen, L., Garcia, P., Sonu, I., Fernandez-Becker, N., Becker, L., Sheth, V., Neshatian, L. 2024: e14781

  Abstract

  Whether patients with defecatory disorders (DDs) with favorable response to a footstool have distinctive anorectal pressure characteristics is unknown. We aimed to identify the clinical phenotype and anorectal pressure profile of patients with DDs who benefit from a footstool.This is a retrospective review of patients with high resolution anorectal manometry (HR-ARM) and balloon expulsion test (BET) from a tertiary referral center. BET was repeated with a 7-inch-high footstool in those who failed it after 120 s. Data were compared among groups with respect to BET results.Of the 667 patients with DDs, a total of 251 (38%) had failed BET. A footstool corrected BET in 41 (16%) of those with failed BET. Gender-specific differences were noted in anorectal pressures, among patients with and without normal BET, revealing gender-based nuances in pathophysiology of DDs. Comparing patients who passed BET with footstool with those who did not, the presence of optimal stool consistency, with reduced instances of loose stools and decreased reliance on laxatives were significant. Additionally, in women who benefited from a footstool, lower anal pressures at rest and simulated defecation were observed. Independent factors associated with a successful BET with a footstool in women included age <50, Bristol 3 or 4 stool consistency, lower anal resting pressure and higher rectoanal pressure gradient.Identification of distinctive clinical and anorectal phenotype of patients who benefited from a footstool could provide insight into the factors influencing the efficacy of footstool utilization and allow for an individualized treatment approach in patients with DDs.

  View details for DOI 10.1111/nmo.14781

  View details for PubMedID 38488172

• Increased Grades of Rectal Intussusception: Role of Decline in Pelvic Floor Integrity and Association with Dyssynergic Defecation. The American journal of gastroenterology Neshatian, L., Triadafilopoulos, G., Wallace, S., Jawahar, A., Sheth, V., Shen, S., Gurland, B. 2023

  Abstract

  The natural history of rectal intussusception (RI) is poorly understood. We hypothesized that decline in pelvic floor integrity and function leads to increasing RI grades.Retrospective analysis of a registry of patients with defecatory disorders with high-resolution anorectal manometry and MR defecography. Association of risk factors on increasing RI grades was assessed using logistic regression.Analysis included a total of 238 women; 90 had no RI, 43 Oxford 1-2, 49 Oxford 3, and 56 Oxford 4-5. Age (p:0.017), vaginal delivery (p: 0.008), and prior pelvic surgery (p: 0.032) were associated with increased Oxford grades. Obstructive defecation symptoms and dyssynergic defecation were observed at relatively high rates across groups. Increased RI grades was associated with less anal relaxation at simulated defecation yet, higher rates of normal balloon expulsion (p<0.05), linked to diminished anal sphincter. Indeed, increased RI grades was associated with worsening fecal incontinence severity, attributed to higher rates of anal hypotension.Levator ani laxity, defined by increased levator hiatus length and its excessive descent at straining, was associated with increasing RI grades, independent of age, history of vaginal delivery, and pelvic surgeries and could independently predict increased RI grades. Concurrent anterior and posterior compartments, and visceral prolapse were associated with higher Oxford grades.Our data suggests that decline in pelvic floor integrity with abnormal levator ani laxity is associated with increased RI grades; a process that is independent of age, history of vaginal deliveries and/or pelvic surgeries, and perhaps related to dyssynergic defecation.

  View details for DOI 10.14309/ajg.0000000000002605

  View details for PubMedID 37975595

• Parametric Response Mapping of Co-Registered Ivim MRI and PET to Identify Radioresistant Sub-Volumes in Locally Advanced Cervical Carcinoma Undergoing CCRT. International journal of radiation oncology, biology, physics Capaldi, D. P., Wang, J. Y., Liu, L., Sheth, V., Kidd, E. A., Hristov, D. H. 2023; 117 (2S): e648

  Abstract

  PURPOSE/OBJECTIVE(S): To investigate parametric response mapping (PRM) of co-registered positron emission tomography (PET) and intravoxel incoherent motion (IVIM) MRI in locally advanced cervical carcinoma patients to identify sub-volumes that may predict treatment response to adjuvant concurrent chemoradiation therapy (CCRT).MATERIALS/METHODS: Pre- and on-treatment (after four weeks of CCRT) diffusion weighted images (DWIs) MRI and pre-treatment PET were performed on 20 cervical cancer patients (median [range] age: 63 [41 to 85]; FIGO staging: 3 IIB, 1 IIIB, 10 IIIC1, 4 IIIC2, 2 IVA; histology: 11 squamous cell carcinoma, 4 endocervical adenocarcinoma; LN status: 4 negative, 16 positive). IVIM MRI maps were generated by Bayesian fitting of a two-compartment IVIM model to the DWIs to produce three-dimensional diffusion coefficient (D) and perfusion fraction (f). Three-dimensional IVIM D and f maps were co-registered to PET standardized uptake value (SUV) maps. Population means of PET SUV, IVIM D and f from pre-treatment scans were calculated to generate thresholds to identify low versus high metabolic (muSUV) regions, low versus high diffused (muD) regions as well as low versus high perfused (muf) regions, respectively. PRM maps were generated using voxel-wise joint histogram analysis to classify voxels within the tumor as highly metabolic and with low cellular density (SUVD), highly metabolic and with high cellular density (SUVD), metabolically inactive and with high cellular density (SUVD), or metabolically inactive and with low cellular density (SUVD) tissue based on the population mean thresholds. Similar PRM maps were generated using the joint histogram analysis with SUV and f. Summary statistics for these and other imaging parameters were calculated pre- and on-treatment. Univariate analysis was performed to determine relationships between relative change in gross tumor volume (DeltaGTV) and pre-treatment imaging measurements.RESULTS: In tumors, on- versus pre-treatment tumor volume (p<.001) significantly decreased, while IVIM f (p = .002) and D (p = .03) significantly increased. Pre-treatment tumor volume (r = .45, p = .04) and PRM SUVD (r = .65, p = .002) regions were positively related with DeltaGTV, while pre-treatment IVIM D (r = -.64, p = .002), PRM SUVf (r = -.52, p = .02) and PRM SUVD (r = -.74, p<.001) regions were negatively related with DeltaGTV. The latter PRM result suggests that larger regions of low cellular density (as represented by elevated D) + low metabolism result in a reduced change in tumor volume on-treatment, potentially representing a radioresistant sub-volume.CONCLUSION: PRM, generated from PET and IVIM MRI, was applied to patients with locally advanced cervical carcinoma and radioresistant sub-volumes were identified which may predict treatment response. The complementary information provided from PET and IVIM, combined using PRM, may assist in decision-making to individualize therapies, such as with image guided brachytherapy, to improve patient outcomes.

  View details for DOI 10.1016/j.ijrobp.2023.06.2067

  View details for PubMedID 37785926

• Anorectal manometry for the diagnosis of pelvic floor disorders in patients with hypermobility spectrum disorders and hypermobile Ehlers-Danlos syndrome. BMC gastroenterology Zhou, W., Zikos, T. A., Halawi, H., Sheth, V. R., Gurland, B., Nguyen, L. A., Neshatian, L. 2022; 22 (1): 538

  Abstract

  INTRODUCTION: Functional gastrointestinal disorders (FGID) including impaired rectal evacuation are common in patients with Hypermobility Spectrum Disorder (HSD) or Hypermobile Ehlers-Danlos Syndrome (hEDS). The effect of connective tissue pathologies on pelvic floor function in HSD/hEDS remains unclear. We aimed to compare clinical characteristics and anorectal pressure profile in patients with HSD/hEDS to those of age and sex matched controls.METHODS: We conducted a retrospective review of all FGID patients who underwent high resolution anorectal manometry (HR-ARM) and balloon expulsion test (BET) for evaluation of impaired rectal evacuation. Patients with HSD/hEDS were age and sex matched to a randomly selected cohort of control patients without HSD/hEDS. An abnormal BET was defined as the inability to expel a rectal balloon within 2minutes. Wilcoxon rank sum test and Fisher's exact test were used to make comparisons and logistic regression model for predictive factors for abnormal evacuation.RESULTS: A total of 144 patients (72 with HSD/hEDS and 72 controls) were analyzed. HSD/hEDS patients were more likely to be Caucasian (p<0.001) and nulliparous. Concurrent psychiatric disorders; depression, and anxiety (p<0.05), and somatic syndromes; fibromyalgia, migraine and sleep disorders (p<0.001) were more common in these patients. Rate of abnormal BET were comparable among the groups. HDS/hEDS patients had significantly less anal relaxation and higher residual anal pressures during simulated defecation, resulting in significantly more negative rectoanal pressure gradient. The remaining anorectal pressure profile and sensory levels were comparable between the groups. While diminished rectoanal pressure gradient was the determinant of abnormal balloon evacuation in non HSD/hEDS patients, increased anal resting tone and maximum volume tolerated were independent factors associated with an abnormal BET in HSD/hEDS patients. Review of defecography data from a subset of patients showed no significant differences in structural pathologies between HSD/hEDS and non HSD/hEDS patients.CONCLUSIONS: These results suggest anorectal pressure profile is not compromised by connective tissue pathologies in HSD patients. Whether concurrent psychosomatic disorders or musculoskeletal involvement impact the pelvic floor function in these patients needs further investigation.

  View details for DOI 10.1186/s12876-022-02572-8

  View details for PubMedID 36564719

• Predictive Value of Clinical Complete Response after Chemoradiation for Rectal Cancer Liu, C., Boncompagni, A. A., Perrone, K., Agarwal, A., Hur, D. G., Lopez, I., Sheth, V., Morris, A. M. LIPPINCOTT WILLIAMS & WILKINS. 2022: S51-S52

  View details for DOI 10.1097/01.XCS.0000893308.54894.46

  View details for Web of Science ID 000867889300080

• Rectosigmoid Cancer-Rectal Cancer or Sigmoid Cancer? American journal of clinical oncology Hui, C., Baclay, R., Liu, K., Sandhu, N., Loo, P., von Eyben, R., Chen, C., Sheth, V., Vitzthum, L., Chang, D., Pollom, E. 2022

  Abstract

  OBJECTIVES: We aimed to determine the optimal treatment for patients with locally advanced rectosigmoid cancers, and to determine whether this can be guided by distance from anal verge (AV) and/or anatomic landmarks such as the sacral promontory and peritoneal reflection (PR).MATERIALS AND METHODS: We retrospectively reviewed patients with T3-T4 and/or node-positive rectosigmoid cancers who underwent surgery from 2006 to 2018 with available pelvic imaging. We included tumors at 9 to 20cm from the AV on either staging imaging, or colonoscopy. Patients were stratified into those who received neoadjuvant therapy, and those who underwent upfront surgery. Comparisons of characteristics were performed using chi2 test and Fischer exact test. Locoregional failure (LRF) and overall survival were compared using Cox regressions and Kaplan-Meier analysis.RESULTS: One hundred sixty-one patients were included. Ninety-seven patients had neoadjuvant therapy, and 64 patients had upfront surgery. Median follow-up time was 45.1 months. Patients who had neoadjuvant therapy had tumors that were higher cT stage (P<0.01) with more positive/close circumferential resection margins seen on imaging by radiologists (28.9% vs. 1.6%, P=0.015). The 2-year rate of LRF, distant metastases, or overall survival was not significantly different between the 2 groups. None of 15 patients with tumors below the PR treated with neoadjuvant therapy had LRF, but 1 (25%) of 4 patients with tumors below the PR treated with adjuvant therapy experienced LRF (P=0.05).CONCLUSIONS: Patients with tumors below the PR may benefit more from neoadjuvant therapy. The PR on imaging may be a reliable landmark in addition to the distance from the AV to determine the most appropriate treatment option.

  View details for DOI 10.1097/COC.0000000000000931

  View details for PubMedID 35848736

• MRI biomarker of muscle composition is associated with severity of pelvic organ prolapse. Techniques in coloproctology Neshatian, L., Lam, J. P., Gurland, B. H., Liang, T., Becker, L., Sheth, V. R. 2022

  Abstract

  BACKGROUND: The pathophysiology of pelvic organ prolapse is largely unknown. We hypothesized that reduced muscle mass on magnetic resonance defecography (MRD) is associated with increased pelvic floor laxity. The aim of this study was to compare the psoas and puborectalis muscle mass composition and cross-sectional area among patients with or without pelvic laxity.METHODS: An observational retrospective study was conducted on women>age 18years old who had undergone MRD for pelvic floor complaints from January 2020 to December 2020 at Stanford Pelvic Health Center. Pelvic floor laxity, pelvic organ descent, and rectal prolapse were characterized by standard measurements on MRD and compared to the psoas (L4 level) and puborectalis muscle index (cross-sectional area adjusted by height) and relative fat fraction, quantified by utilizing a 2-point Dixon technique. Regression analysis was used to quantify the association between muscle characteristics and pelvic organ measurements.RESULTS: The psoas fat fraction was significantly elevated in patients with abnormally increased resting and strain H and M lines (p<0.05) and increased with rising grades of Oxford rectal prolapse (p=0.0001), uterovaginal descent (p=0.001) and bladder descent (p=0.0005). In multivariate regression analysis, adjusted for age and body mass index, the psoas fat fraction (not muscle index) was an independent risk factor for abnormal strain H and M line; odds ratio (95% confidence interval) of 17.8 (2-155.4) and 18.5 (1.3-258.3) respectively, and rising Oxford grade of rectal prolapse 153.9 (4.4-5383) and bladder descent 12.4 (1.5-106). Puborectalis fat fraction was increased by rising grades of Oxford rectal prolapse (p=0.0002).CONCLUSIONS: Severity of pelvic organ prolapse appears to be associated with increasing psoas muscle fat fraction, a biomarker for reduced skeletal muscle mass. Future prospective research is needed to determine if sarcopenia may predict postsurgical outcomes after pelvic organ prolapse repair.

  View details for DOI 10.1007/s10151-022-02651-8

  View details for PubMedID 35727428

• Editorial for "Amide Proton Transfer-Weighted Imaging Combined With Intravoxel Incoherent Motion for Evaluating Microsatellite Instability in Endometrial Cancer". Journal of magnetic resonance imaging : JMRI Sheth, V. R. 2022

  View details for DOI 10.1002/jmri.28302

  View details for PubMedID 35713324

• Phase II trial of organ preservation program using short-course radiation and folfoxiri for rectal cancer (SHORT-FOX) Pollom, E. L., Shelton, A., Fisher, G. A., Bien, J., King, D., Johnson, T., Chen, C., Shaheen, S., Chong, C., Vitzthum, L., Kirilcuk, N., Morris, A. M., Kin, C., Dawes, A., Sheth, V., Sundaram, V., Brown, E., Chang, D. LIPPINCOTT WILLIAMS & WILKINS. 2022

  View details for DOI 10.1200/JCO.2022.40.4_suppl.TPS218

  View details for Web of Science ID 000770995900213

• Establishment of Patient-derived Succinate Dehydrogenase-deficient Gastrointestinal Stromal Tumor Models For Predicting Therapeutic Response. Clinical cancer research : an official journal of the American Association for Cancer Research Yebra, M., Bhargava, S., Kumar, A., Burgoyne, A. M., Tang, C., Yoon, H., Banerjee, S., Aguilera, J., Cordes, T., Sheth, V., Noh, S., Ustoy, R., Li, S., Advani, S. J., Corless, C. L., Heinrich, M. C., Kurzrock, R., Lippman, S. M., Fanta, P. T., Harismendy, O., Metallo, C., Sicklick, J. K. 2021

  Abstract

  PURPOSE: Gastrointestinal stromal tumor (GIST) is the most common sarcoma of the gastrointestinal tract with mutant succinate dehydrogenase (SDH) subunits (A-D) comprising less than 7.5% (i.e. 150-200/year) of new cases annually in the United States. Contrary to GISTs harboring KIT or PDGFRA mutations, SDH-mutant GISTs affect adolescents/young adults, often metastasize, and are frequently resistant to tyrosine kinase inhibitors (TKIs). Lack of human models for any SDH-mutant tumors, including GIST, has limited molecular characterization and drug discovery.EXPERIMENTAL DESIGN: We describe methods for establishing novel patient-derived SDH-mutant (mSDH) GIST models and interrogated the efficacy of temozolomide on these tumor models in vitro and in clinical trials of mSDH GIST patients.RESULTS: Molecular and metabolic characterization of our patient-derived mSDH GIST models revealed that these models recapitulate the transcriptional and metabolic hallmarks of parent tumors and SDH-deficiency. We further demonstrate that temozolomide elicits DNA damage and apoptosis in our mSDH GIST models. Translating our in vitro discovery to the clinic, a cohort of SDH-mutant GIST patients treated with temozolomide (n=5) demonstrated a 40% objective response rate and 100% disease control rate suggesting that temozolomide represents a promising therapy for this subset of GIST.CONCLUSION: We report the first methods to establish patient-derived mSDH tumor models, which can be readily employed for understanding patient-specific tumor biology and treatment strategies. We also demonstrate that temozolomide is effective in mSDH GIST patients who are refractory to existing chemotherapeutic drugs (namely TKIs) in clinic for GISTs, bringing a promising treatment option for these patients to clinic.

  View details for DOI 10.1158/1078-0432.CCR-21-2092

  View details for PubMedID 34426440

• Adult residual rectourethral fistula and diverticulum presenting decades after imperforate anus repair: acase report. Journal of medical case reports McShane, E. K., Gurland, B., Sheth, V. R., Bruzoni, M., Enemchukwu, E. 2021; 15 (1): 370

  Abstract

  BACKGROUND: This report describes a rare surgical case of an intraabdominal mass in a middle-aged patient 40years after imperforate anus repair.CASE PRESENTATION: A 44-year-old Latino male with history of repaired anorectal malformation presented with recurrent urinary tract infections and rectal prolapse with bothersome bleeding and fecal incontinence. During his preoperative evaluation, he was initially diagnosed with a prostatic utricle cyst on the basis of magnetic resonance imaging findings, which demonstrated a cystic, thick-walled mass with low signal contents that extended inferiorly to insert into the distal prostatic urethra. However, at the time of surgical resection, the thick-walled structure contained an old, firm fecaloma. The final pathology report described findings consistent with colonic tissue, suggesting a retained remnant of the original fistula and diverticulum.CONCLUSIONS: Although rare, persistent rectourethral fistula tracts and rectal diverticula after imperforate anus repair can cause symptoms decades later, requiring surgical intervention. This is an important diagnostic consideration for any adult patient with history of imperforate anus.

  View details for DOI 10.1186/s13256-021-02921-3

  View details for PubMedID 34261520

• Extending Reach Inside the MRI Bore: A 7-DOF, Low-Friction, Hydrostatic Teleoperator S, F., RD, I., V, S., BL, D., MR, C. IEEE Transactions on Medical Robotics and Bionics . 2021

  Abstract

  3:701–713. Winner of the 2021 IEEE T-MRB Best Paper Award

• Evaluation of cortical bone perfusion using dynamic contrast enhanced ultrashort echo time imaging: a feasibility study. Quantitative imaging in medicine and surgery Wan, L., Wu, M., Sheth, V., Shao, H., Jang, H., Bydder, G., Du, J. 2019; 9 (8): 1383-1393

  Abstract

  Dynamic contrast enhanced magnetic resonance imaging (DCE-MRI) has been used to study perfusion in a wide variety of soft tissues including the bone marrow. Study of perfusion in hard tissues such as cortical bone has been much more limited because of the lack of detectable MR signal from them using conventional pulse sequences. However, two-dimensional (2D) ultrashort echo time (UTE) sequences detect signal from cortical bone and allow fast imaging of this tissue. In addition, adiabatic 2D inversion recovery UTE (IR-UTE) sequences can provide excellent signal suppression of soft tissues, such as muscle and marrow, and allow cortical bone to be seen with high contrast and reduced artefacts. We aimed to assess the feasibility of using 2D UTE and 2D IR-UTE sequences to perform DCE-MRI in the cortical bone of rabbits and human volunteers.Cortical bone perfusion was studied in rabbits (n=12) and human volunteers (n=3) using 2D UTE and 2D IR-UTE sequences on a clinical 3T scanner. Dynamic data with an in-plane resolution of ~0.5×0.5 mm2, single slice thickness of 3 mm for rabbits and 10 mm for human volunteers, and temporal resolution of 23 s for 2D UTE imaging of rabbits, 28 s for 2D UTE imaging of human volunteers, and 60 s for 2D IR-UTE imaging of both the rabbits and human volunteers were acquired before and after the injection of a Gd contrast agent (Gd-BOPTA: Multihance; Bracco Imaging SpA, Milan, Italy). The dose was 0.06 mmol/kg for rabbits and 0.2 mmol/kg for human subjects. Kinetic analyses based on the Brix model, as well as simple calculations of maximum enhancement (ME) and enhancement slope (ES), were performed.The 12 rabbits showed a mean Ktrans of 0.36±0.07 min-1, Kep of 8.42±3.17 min-1, ME of 28.30±6.83, ES of 0.35±0.18 for the femur with the 2D UTE sequence, and a mean Ktrans of 0.45±0.10 min-1, Kep of 9.80±0.50 min-1, ME of 48.84±12.12, and ES of 0.69±0.27 for the femur with the 2D IR-UTE sequence. Lower ME and ES values were observed in the tibial midshaft of healthy human volunteers compared to rabbits.These results show that 2D UTE and 2D IR-UTE sequences are capable of detecting dynamic contrast enhancement in cortical bone in both rabbits and healthy human volunteers. Clinical studies with these techniques are likely to be feasible.

  View details for DOI 10.21037/qims.2019.08.05

  View details for PubMedID 31559167

  View details for PubMedCentralID PMC6732064

• Multimodal imaging assessment and histologic correlation of the female rat pelvic floor muscles' anatomy. Journal of anatomy Sheth, V. R., Duran, P., Wong, J., Shah, S., Du, J., Christman, K. L., Chang, E. Y., Alperin, M. 2019; 234 (4): 543-550

  Abstract

  Pelvic floor disorders negatively impact millions of women worldwide. Although there is a strong epidemiological association with childbirth, the mechanisms leading to the dysfunction of the integral constituents of the female pelvic floor, including pelvic floor skeletal muscles, are not well understood. This is in part due to the constraints associated with directly probing these muscles, which are located deep in the pelvis. Thus, experimental models and non-invasive techniques are essential for advancing knowledge of various phenotypes of pelvic floor muscle injury and pathogenesis of muscle dysfunction, as well as developing minimally invasive approaches for the delivery of novel therapeutics. The most widely used animal model for pelvic floor disorders is the rat. However, the radiological anatomy of rat pelvic floor muscles has not been described. To remedy this gap, the current study provides the first detailed description of the female rat pelvic floor muscles' radiological appearance on MR and ultrasound images, validated by correlation with gross anatomy and histology. We also demonstrate that ultrasound guidance can be used to target rat pelvic floor muscles for possible interventional therapies.

  View details for DOI 10.1111/joa.12943

  View details for PubMedID 30740685

  View details for PubMedCentralID PMC6422690

• Data-driven self-calibration and reconstruction for non-cartesian wave-encoded single-shot fast spin echo using deep learning. Journal of magnetic resonance imaging : JMRI Chen, F. n., Cheng, J. Y., Taviani, V. n., Sheth, V. R., Brunsing, R. L., Pauly, J. M., Vasanawala, S. S. 2019

  Abstract

  Current self-calibration and reconstruction methods for wave-encoded single-shot fast spin echo imaging (SSFSE) requires long computational time, especially when high accuracy is needed.To develop and investigate the clinical feasibility of data-driven self-calibration and reconstruction of wave-encoded SSFSE imaging for computation time reduction and quality improvement.Prospective controlled clinical trial.With Institutional Review Board approval, the proposed method was assessed on 29 consecutive adult patients (18 males, 11 females, range, 24-77 years).A wave-encoded variable-density SSFSE sequence was developed for clinical 3.0T abdominal scans to enable 3.5× acceleration with full-Fourier acquisitions. Data-driven calibration of wave-encoding point-spread function (PSF) was developed using a trained deep neural network. Data-driven reconstruction was developed with another set of neural networks based on the calibrated wave-encoding PSF. Training of the calibration and reconstruction networks was performed on 15,783 2D wave-encoded SSFSE abdominal images.Image quality of the proposed data-driven approach was compared independently and blindly with a conventional approach using iterative self-calibration and reconstruction with parallel imaging and compressed sensing by three radiologists on a scale from -2 to 2 for noise, contrast, sharpness, artifacts, and confidence. Computation time of these two approaches was also compared.Wilcoxon signed-rank tests were used to compare image quality and two-tailed t-tests were used to compare computation time with P values of under 0.05 considered statistically significant.An average 2.1-fold speedup in computation was achieved using the proposed method. The proposed data-driven self-calibration and reconstruction approach significantly reduced the perceived noise level (mean scores 0.82, P < 0.0001).The proposed data-driven calibration and reconstruction achieved twice faster computation with reduced perceived noise, providing a fast and robust self-calibration and reconstruction for clinical abdominal SSFSE imaging.1 Technical Efficacy: Stage 1 J. Magn. Reson. Imaging 2019.

  View details for DOI 10.1002/jmri.26871

  View details for PubMedID 31322799

• Near-silent distortionless DWI using magnetization-prepared RUFIS. Magnetic resonance in medicine Yuan, J. n., Hu, Y. n., Menini, A. n., Sandino, C. M., Sandberg, J. n., Sheth, V. n., Moran, C. J., Alley, M. n., Lustig, M. n., Hargreaves, B. n., Vasanawala, S. n. 2019

  Abstract

  To develop a near-silent and distortionless DWI (sd-DWI) sequence using magnetization-prepared rotating ultrafast imaging sequence.A rotating ultrafast imaging sequence was modified with driven-equilibrium diffusion preparation, including eddy-current compensation methods. To compensate for the T1 recovery during readout, a phase-cycling method was used. Both compensation methods were validated in phantoms. The optimized sequence was compared with an EPI diffusion sequence for image distortion, contrast, ADC, and acoustic noise level in phantoms. The sequence was evaluated in 1 brain volunteer, 5 prostate volunteers, and 10 pediatric patients with joint diseases.Combination of several eddy-current compensation methods reduced the artifact to an acceptable level. Phase cycling reduced T1 recovery contamination during readout. In phantom scans, the optimized sequence generated similar image contrast to the EPI diffusion sequence, and ADC maps between the sequences were comparable; sd-DWI had significantly lower acoustic noise (P < .05). In vivo brain scan showed reduced image distortion in sd-DWI compared with the EPI diffusion, although residual motion artifact remains due to brain pulsation. The prostate scans showed that sd-DWI can provide similar ADC compared with EPI diffusion, with no image distortion. Patient scans showed that the sequence can clearly depict joint lesions.An sd-DWI sequence was developed and optimized. Compared with conventional EPI diffusion, sd-DWI provided similar diffusion contrast, accurate ADC measurement, improved image quality, and minimal ambient scanning noise. The sequence showed the ability to obtain in vivo diffusion contrast in relatively motion-free body regions, such as prostate and joint.

  View details for DOI 10.1002/mrm.28106

  View details for PubMedID 31782557

• Direct magnitude and phase imaging of myelin using ultrashort echo time (UTE) pulse sequences: A feasibility study. Magnetic resonance imaging He, Q., Ma, Y., Fan, S., Shao, H., Sheth, V., Bydder, G. M., Du, J. 2017; 39: 194-199

  Abstract

  In this paper, we aimed to investigate the feasibility of direct visualization of myelin, including myelin lipid and myelin basic protein (MBP), using two-dimensional ultrashort echo time (2D UTE) sequences and utilize phase information as a contrast mechanism in phantoms and in volunteers. The standard UTE sequence was used to detect both myelin and long T2 signal. An adiabatic inversion recovery UTE (IR-UTE) sequence was used to selectively detect myelin by suppressing signal from long T2 water protons. Magnitude and phase imaging and T2* were investigated on myelin lipid and MBP in the forms of lyophilized powders as well as paste-like phantoms with the powder mixed with D2O, and rubber phantoms as well as healthy volunteers. Contrast to noise ratio (CNR) between white and gray matter was measured. Both magnitude and phase images were generated for myelin and rubber phantoms as well white matter in vivo using the IR-UTE sequence. T2* values of ~300μs were comparable for myelin paste phantoms and the short T2* component in white matter of the brain in vivo. Mean CNR between white and gray matter in IR-UTE imaging was increased from -7.3 for the magnitude images to 57.4 for the phase images. The preliminary results suggest that the IR-UTE sequence allows simultaneous magnitude and phase imaging of myelin in vitro and in vivo.

  View details for DOI 10.1016/j.mri.2017.02.009

  View details for PubMedID 28219648

  View details for PubMedCentralID PMC5503674

• Inversion recovery ultrashort echo time magnetic resonance imaging: A method for simultaneous direct detection of myelin and high signal demonstration of iron deposition in the brain - A feasibility study. Magnetic resonance imaging Sheth, V. R., Fan, S., He, Q., Ma, Y., Annese, J., Switzer, R., Corey-Bloom, J., Bydder, G. M., Du, J. 2017; 38: 87-94

  Abstract

  Multiple sclerosis (MS) causes demyelinating lesions in the white matter and increased iron deposition in the subcortical gray matter. Myelin protons have an extremely short T2* (<1ms) and are not directly detected with conventional clinical magnetic resonance (MR) imaging sequences. Iron deposition also reduces T2*, leading to reduced signal on clinical sequences. In this study we tested the hypothesis that the inversion recovery ultrashort echo time (IR-UTE) pulse sequence can directly and simultaneously image myelin and iron deposition using a clinical 3T scanner. The technique was first validated on a synthetic myelin phantom (myelin powder in D2O) and a Feridex iron phantom. This was followed by studies of cadaveric MS specimens, healthy volunteers and MS patients. UTE imaging of the synthetic myelin phantom showed an excellent bi-component signal decay with two populations of protons, one with a T2* of 1.2ms (residual water protons) and the other with a T2* of 290μs (myelin protons). IR-UTE imaging shows sensitivity to a wide range of iron concentrations from 0.5 to ~30mM. The IR-UTE signal from white matter of the brain of healthy volunteers shows a rapid signal decay with a short T2* of ~300μs, consistent with the T2* values of myelin protons in the synthetic myelin phantom. IR-UTE imaging in MS brain specimens and patients showed multiple white matter lesions as well as areas of high signal in subcortical gray matter. This in specimens corresponded in position to Perl's diaminobenzide staining results, consistent with increased iron deposition. IR-UTE imaging simultaneously detects lesions with myelin loss in the white matter and iron deposition in the gray matter.

  View details for DOI 10.1016/j.mri.2016.12.025

  View details for PubMedID 28038965

  View details for PubMedCentralID PMC5503675

• Magnetic resonance imaging of myelin using ultrashort Echo time (UTE) pulse sequences: Phantom, specimen, volunteer and multiple sclerosis patient studies. NeuroImage Sheth, V., Shao, H., Chen, J., Vandenberg, S., Corey-Bloom, J., Bydder, G. M., Du, J. 2016; 136: 37-44

  Abstract

  Clinical magnetic resonance imaging of multiple sclerosis (MS) has focused on indirect imaging of myelin in white matter by detecting signal from protons in the water associated with myelin. Here we show that protons in myelin can be directly imaged using ultrashort echo time (UTE) free induction decay (FID) and imaging sequences on a clinical 3T MR scanner. An adiabatic inversion recovery UTE (IR-UTE) sequence was used to detect signal from myelin and simultaneously suppress signal from water protons. Validation studies were performed on myelin lipid and myelin basic protein (MBP) phantoms in the forms of lyophilized powders as well as suspensions in D2O and H2O. IR-UTE sequences were then used to image MS brain specimens, healthy volunteers, and patients. The T2* of myelin was measured using a UTE FID sequence, as well as UTE and IR-UTE sequences at different TEs. T2* values of ~110-330μs were measured with UTE FID, as well as with UTE and IR-UTE sequences for myelin powders, myelin-D2O and myelin-H2O phantoms, consistent with selective imaging of myelin protons with IR-UTE sequences. Our studies showed myelin selective imaging of white matter in the brains in vitro and in vivo. Complete or partial signal loss was observed in specimens in areas of the brain with histopathologic evidence of myelin loss, and in the brain of patients with MS.

  View details for DOI 10.1016/j.neuroimage.2016.05.012

  View details for PubMedID 27155128

  View details for PubMedCentralID PMC4914437

• Chapter 2 Positron Emission Tomography – Magnetic Resonance Imaging Molecular Imaging: Principles and Practice F, M., RL, B., VL, S., A, I. 2016
• Measurement of T1 of the ultrashort T2* components in white matter of the brain at 3T. PloS one Du, J., Sheth, V., He, Q., Carl, M., Chen, J., Corey-Bloom, J., Bydder, G. M. 2014; 9 (8): e103296

  Abstract

  Recent research demonstrates that white matter of the brain contains not only long T2 components, but a minority of ultrashort T2* components. Adiabatic inversion recovery prepared dual echo ultrashort echo time (IR-dUTE) sequences can be used to selectively image the ultrashort T2* components in white matter of the brain using a clinical whole body scanner. The T2*s of the ultrashort T2* components can be quantified using mono-exponential decay fitting of the IR-dUTE signal at a series of different TEs. However, accurate T1 measurement of the ultrashort T2* components is technically challenging. Efficient suppression of the signal from the majority of long T2 components is essential for robust T1 measurement. In this paper we describe a novel approach to this problem based on the use of IR-dUTE data acquisitions with different TR and TI combinations to selectively detect the signal recovery of the ultrashort T2* components. Exponential recovery curve fitting provides efficient T1 estimation, with minimized contamination from the majority of long T2 components. A rubber phantom and a piece of bovine cortical bone were used for validation of this approach. Six healthy volunteers were studied. An averaged T2* of 0.32 ± 0.09 ms, and a short mean T1 of 226 ± 46 ms were demonstrated for the healthy volunteers at 3T.

  View details for DOI 10.1371/journal.pone.0103296

  View details for PubMedID 25093859

  View details for PubMedCentralID PMC4122467

• Detection of in vivo enzyme activity with CatalyCEST MRI. Magnetic resonance in medicine Yoo, B., Sheth, V. R., Howison, C. M., Douglas, M. J., Pineda, C. T., Maine, E. A., Baker, A. F., Pagel, M. D. 2014; 71 (3): 1221-30

  Abstract

  CatalyCEST MRI compares the detection of an enzyme-responsive chemical exchange saturation transfer (CEST) agent with the detection of an unresponsive "control" CEST agent that accounts for other conditions that influence CEST. The purpose of this study was to investigate the feasibility of in vivo catalyCEST MRI.CEST agents that were responsive and unresponsive to the activity of urokinase plasminogen activator were shown to have negligible interaction with each other. A CEST-fast imaging with steady state precession (FISP) MRI protocol was used to acquire MR CEST spectroscopic images with a Capan-2 pancreatic tumor model after intravenous injection of the CEST agents. A function of (super)-Lorentzian line shapes was fit to CEST spectra of a region-of-interest that represented the tumor.The CEST effects from each agent showed the same initial uptake into tumor tissues, indicating that both agents had the same pharmacokinetic transport rates. Starting 5 min after injection, CEST from the enzyme-responsive agent disappeared more quickly than CEST from the unresponsive agent, indicating that the enzyme responsive agent was being catalyzed by urokinase plasminogen activator, while both agents also experienced net pharmacokinetic washout from the tumor.CatalyCEST MRI demonstrates that dynamic tracking of enzyme-responsive and unresponsive CEST agents during the same in vivo MRI study is feasible.

  View details for DOI 10.1002/mrm.24763

  View details for PubMedID 23640714

  View details for PubMedCentralID PMC3742626

• Measuring in vivo tumor pHe with CEST-FISP MRI. Magnetic resonance in medicine Sheth, V. R., Li, Y., Chen, L. Q., Howison, C. M., Flask, C. A., Pagel, M. D. 2012; 67 (3): 760-8

  Abstract

  Paramagnetic chemical exchange saturation transfer (PARACEST) MRI contrast agents have been developed that can measure pH in solution studies, but these agents have not previously been detected in vivo. To use the PARACEST agent Yb-DO3A-oAA to measure the extracellular pH (pHe) in tumor tissue, a chemical exchange saturation transfer fast imaging with steady state precession MRI protocol was developed, the saturation period was optimized for sensitive chemical exchange saturation transfer (CEST) detection, and median filtering was used to remove artifacts in CEST spectra. These improvements were used to correlate pH with a ratio of two CEST effects of Yb-DO3A-oAA at a 7 T magnetic field strength (R(2) = 0.99, standard deviation of precision = 0.011 pH units). The PARACEST agent could not be detected in tumor tissue following i.v. injection due to the low sensitivity of in vivo CEST MRI. Yb-DO3A-oAA was detected in tumor tissue and leg muscle after directly injecting the PARACEST agent into these tissues. The measured CEST effects were used to measure a tumor pH of 6.82 ± 0.21 and a leg muscle pH of 7.26 ± 0.14, and parametric pH maps were also generated from these tissue regions. These results demonstrated that tumor pHe can be measured with a PARACEST agent and a rapid CEST-MRI protocol.

  View details for DOI 10.1002/mrm.23038

  View details for PubMedID 22028287

  View details for PubMedCentralID PMC3572795

• Improved pH measurements with a single PARACEST MRI contrast agent. Contrast media & molecular imaging Sheth, V. R., Liu, G., Li, Y., Pagel, M. D. 2012; 7 (1): 26-34

  Abstract

  The measurement of extracellular pH has potential utility for assessing the therapeutic effects of pH-dependent and pH-altering therapies. A PARAmagnetic chemical exchange saturation transfer (PARACEST) MRI contrast agent, Yb-DO3A-oAA, has two CEST effects that are dependent on pH. A ratio derived from these CEST effects was linearly correlated with pH throughout the physiological pH range. The pH can be measured with a precision of 0.21 pH units and an accuracy of 0.09 pH units. The pH measurement is independent of concentration and T₁ relaxation times, but is dependent on temperature. Although MR coalescence affects the CEST measurements, especially at high pH, the ratiometric analysis of the CEST effects can account for incomplete saturation of the agent's amide and amine that results from MR coalescence. Provided that an empirical calibration is determined with saturation conditions, magnetic field strength and temperature that can be used for subsequent studies, these results demonstrate that this single PARACEST MRI contrast agent can accurately measure pH.

  View details for DOI 10.1002/cmmi.460

  View details for PubMedID 22344877

  View details for PubMedCentralID PMC4882612

• Imaging in vivo extracellular pH with a single paramagnetic chemical exchange saturation transfer magnetic resonance imaging contrast agent. Molecular imaging Liu, G., Li, Y., Sheth, V. R., Pagel, M. D. 2012; 11 (1): 47-57

  Abstract

  The measurement of extracellular pH (pHe) has potential utility for cancer diagnoses and for assessing the therapeutic effects of pH-dependent therapies. A single magnetic resonance imaging (MRI) contrast agent that is detected through paramagnetic chemical exchange saturation transfer (PARACEST) was designed to measure tumor pH(e) throughout the range of physiologic pH and with magnetic resonance saturation powers that are not harmful to a mouse model of cancer. The chemical characterization and modeling of the contrast agent Yb(3+)-1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid,10-o-aminoanilide (Yb-DO3A-oAA) suggested that the aryl amine of the agent forms an intramolecular hydrogen bond with a proximal carboxylate ligand, which was essential for generating a practical chemical exchange saturation transfer (CEST) effect from an amine. A ratio of CEST effects from the aryl amine and amide was linearly correlated with pH throughout the physiologic pH range. The pH calibration was used to produce a parametric pH map of a subcutaneous flank tumor on a mouse model of MCF-7 mammary carcinoma. Although refinements in the in vivo CEST MRI methodology may improve the accuracy of pHe measurements, this study demonstrated that the PARACEST contrast agent can be used to generate parametric pH maps of in vivo tumors with saturation power levels that are not harmful to a mouse model of cancer.

  View details for PubMedID 22418027

  View details for PubMedCentralID PMC4876950

• Chapter 24: CEST & PARACEST Agents for Imaging Cancer Biomarkers Molecular Imaging Probes for Cancer Research VR, S., MD, P. 2012
• A self-calibrating PARACEST MRI contrast agent that detects esterase enzyme activity. Contrast media & molecular imaging Li, Y., Sheth, V. R., Liu, G., Pagel, M. D. 2010; 6 (4): 219-28

  Abstract

  The CEST effect of many PARACEST MRI contrast agents changes in response to a molecular biomarker. However, other molecular biomarkers or environmental factors can influence CEST, so that a change in CEST is not conclusive proof for detecting the biomarker. To overcome this problem, a second control CEST effect may be included in the same PARACEST agent, which is responsive to all factors that alter the first CEST effect except for the biomarker to be measured. To investigate this approach, a PARACEST MRI contrast agent was developed with one CEST effect that is responsive to esterase enzyme activity and a second control CEST effect. The ratio of the two CEST effects was independent of concentration and T(1) relaxation, so that this agent was self-calibrating with respect to these factors. This ratiometric method was dependent on temperature and was influenced by MR coalescence as the chemical exchange rates approached the chemical shifts of the exchangable protons as temperature was increased. The two CEST effects also showed evidence of having different pH dependencies, so that this agent was not self-calibrating with respect to pH. Therefore, a self-calibrating PARACEST MRI contrast agent can more accurately detect a molecular biomarker such as esterase enzyme activity, as long as temperature and pH are within an acceptable physiological range and remain constant.

  View details for DOI 10.1002/cmmi.421

  View details for PubMedID 21861282

  View details for PubMedCentralID PMC4879975

• An amine-derivatized, DOTA-loaded polymeric support for Fmoc Solid Phase Peptide Synthesis. Tetrahedron letters Yoo, B., Sheth, V. R., Pagel, M. D. 2009; 50 (31): 4459-4462

  Abstract

  An amine-derivatized DOTA has been used to modify the surface of a polymeric support for conventional Solid Phase Peptide Synthesis (SPPS) following standard Fmoc chemistry methods. This methodology was used to synthesize a peptide-DOTA conjugate that was demonstrated to be a PARACEST MRI contrast agent. Therefore, this synthesis methodology can facilitate Fmoc SPPS of molecular imaging contrast agents.

  View details for DOI 10.1016/j.tetlet.2009.05.061

  View details for PubMedID 20161272

  View details for PubMedCentralID PMC2702766

• Monitoring infection and inflammation in murine models of cystic fibrosis with magnetic resonance imaging. Journal of magnetic resonance imaging : JMRI Sheth, V. R., van Heeckeren, R. C., Wilson, A. G., van Heeckeren, A. M., Pagel, M. D. 2008; 28 (2): 527-32

  Abstract

  To evaluate magnetic resonance imaging (MRI) in assessing lung inflammation longitudinally in genetic mouse models of cystic fibrosis (CF). MRI is used to view soft tissues noninvasively, but the lung is challenging to image.Cftr(+/+) (wildtype) and Cftr(-/-) (CF) mice were inoculated with agarose beads laden with Pseudomonas aeruginosa. Longitudinal MR lung images were acquired with cardiac gating. The effects of echo time and respiration gating were evaluated to improve the detection of lung inflammation.Cardiac gating and signal averaging sufficiently suppressed motion artifacts without requiring respiration gating. MRI detected moderate to severe inflammation in infected mice, which was confirmed by histology results.In vivo longitudinal MRI methods can assess lung inflammation in P. aeruginosa-infected mice, which obviates serial sacrifice. MRI was able to detect inflammation in the absence of other physiological symptoms.

  View details for DOI 10.1002/jmri.21440

  View details for PubMedID 18666218

  View details for PubMedCentralID PMC2538376