Publications by authors named "Maryam Aghighi"

17 Publications

  • Page 1 of 1

Cutaneous desmoid-type fibromatosis: a rare case with molecular profiling.

J Cutan Pathol 2021 May 12. Epub 2021 May 12.

Department of Pathology, Stanford University, Stanford, California.

Fibromatoses encompass a broad group of histopathologically similar fibroblastic/myofibroblastic proliferations with divergent clinical manifestations and behavior. Deep (desmoid-type) fibromatoses are typically large, rapidly growing, and locally aggressive tumors that occur in the abdominal wall, mesentery, and extraabdominal soft tissue, principally the musculature of the trunk and extremities. Most sporadic cases of desmoid fibromatosis harbor inactivating mutations in CTNNB1, the gene encoding beta-catenin. Tumors occurring in the context of familial adenomatous polyposis and Gardner syndrome bear inactivating mutations in APC. By contrast, mutations in CTNNB1 or APC have not been identified in cases of superficial fibromatosis. Cutaneous involvement by desmoid fibromatosis is exceedingly rare. Here we present a 78-year-old male with desmoid-type fibromatosis arising in the dermis of the right medial calf with a pathogenic mutation in CTNNB1 and a variant of unknown significance in APC. This article is protected by copyright. All rights reserved.
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http://dx.doi.org/10.1111/cup.14058DOI Listing
May 2021

Immunohistochemical Expression of Galectin-3 in Pemphigus Vulgaris.

Am J Dermatopathol 2021 Mar 9. Epub 2021 Mar 9.

Department of Pathology, Robert Wood Johnson Barnabas Health, Livingston, NJ; and Department of Pathology, University of Rochester School of Medicine and Dentistry, Rochester, NY.

Abstract: Pemphigus vulgaris (PV) is an autoimmune bullous disorder related to immunoglobulin-G autoantibodies against desmoglein-3. Galectin-3 is one of the main elements of the immunoglobulin-E group which is essential in the cell-cell or cell-matrix adhesion. Although the presence of immunoglobulin-E autoantibodies in PV has been observed, no studies have been performed to describe the role of galectin-3 in PV. We evaluated galectin-3 expression in PV as a first step in assessing its impact in the pathogenesis of this autoimmune blistering process. In a retrospective study, 56 specimens from 45 patients diagnosed with PV were stained with antibodies to galectin-3. The percentages of nuclear and cytoplasmic galectin-3 expression as well as staining intensity were evaluated around blisters and adjacent unaffected skin. We observed a significant decrease in galectin-3 cytoplasmic and nuclear expression as well as stain intensity around blisters compared with adjacent unaffected skin. Although autoantibodies against desmogleins trigger the blister formation in PV patients, loss of galectin-3 may play a role in the extension of blister formation by initiating cell-cell disassembly at the level of the intercellular keratinocyte desmosome. We demonstrated a lower expression of galectin-3 around the blisters in PV. The pathogenesis of the blister formation may be related to lower expression of galectin-3. Additional studies are necessary to clarify the result of this outcome and determine the accurate pathogenesis of blister formation in PV.
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http://dx.doi.org/10.1097/DAD.0000000000001939DOI Listing
March 2021

Diminished Expression of Galectin-3 Around Blisters in Bullous Pemphigoid: An Immunohistochemistry Study.

Dermatol Pract Concept 2020 Oct 26;10(4):e2020106. Epub 2020 Oct 26.

Department of Pathology, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA.

Background: Bullous pemphigoid (BP) is a subepidermal blistering disorder caused by autoantibodies directed against hemidesmosomal proteins. Many patients with BP demonstrate circulating IgE autoantibodies. Although the role of IgE in the pathogenesis of BP is unknown, a correlation between IgE antibodies and eosinophilia has been observed. Soluble CD23 and galectin-3 are the main elements of the IgE group. The roles for CD23 in BP as a potential biomarker and IgE production regulator have been characterized, but no studies have evaluated any roles for galectin-3 in this disease.

Objective: In this study, we evaluated galectin-3 expression in BP as a first step in assessing its role in the pathogenesis of this autoimmune blistering process.

Patients And Methods: Sixty specimens diagnosed as BP were stained with antibodies to galectin-3. The percentages of nuclear and cytoplasmic galectin-3 expression and staining intensity were evaluated.

Results: There was a significant difference in galectin-3 cytoplasmic and nuclear expression within keratinocytes immediately surrounding and above the blisters: (1) cytoplasmic (mean = 17.2% ± 2.4%) vs adjacent unaffected skin (mean = 66.7% ± 2.0%, P < 0.0001) and (2) nuclear (mean = 1.9% ± 0.4%) vs adjacent unaffected skin (mean = 13.2% ± 1.2%, P < 0.0001).

Conclusions: Lower expression of galectin-3 around blisters in BP may suggest a role as an adhesion molecule. Loss of galectin-3 may add to the extension of blister formation by initiating cell-extracellular matrix disassembly and may be involved with the associated dermal inflammation and the eosinophil chemotaxis. Further studies will be necessary to elucidate the result of this observed loss on disease pathogenesis.
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http://dx.doi.org/10.5826/dpc.1004a106DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7588160PMC
October 2020

An Uncommon Case of Lichen Spinulosus in an Adult Patient Clinically Mmimicking Folliculotropic Mycosis Fungoides.

Cureus 2020 Jun 12;12(6):e8572. Epub 2020 Jun 12.

Pathology and Dermatology, University of Rochester School of Medicine and Dentistry, Rochester, USA.

Lichen spinulosus (LS) is an uncommon skin condition mostly in children and adolescents but uncommon in adults. It presents as a group of hypopigmented or skin-colored follicular papules and keratotic spines with a sandpaper-like appearance. There is a lymphohistiocytic infiltrate in the dermis centered around hair follicles. We present a rare case of LS in a 52-year-old woman with a rough, bumpy, itchy rash affecting the trunk and extremities. Her rash consisted of clusters of hyperkeratotic follicular-based spiny papules. Histologic sections demonstrated several dilated hair follicles filled with keratotic plugs surrounded by a dense perifollicular lymphohistiocytic infiltrate, particularly at the level of the infundibula, that extended into the follicular epithelium.
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http://dx.doi.org/10.7759/cureus.8572DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7358940PMC
June 2020

Brain iron deposition after Ferumoxytol-enhanced MRI: A study of Porcine Brains.

Nanotheranostics 2020 18;4(4):195-200. Epub 2020 Jun 18.

Department of Radiology, Molecular Imaging Program at Stanford, Stanford University, CA, USA.

Recent evidence of gadolinium deposition in the brain has raised safety concerns. Iron oxide nanoparticles are re-emerging as promising alternative MR contrast agents, because the iron core can be metabolized. However, long-term follow up studies of the brain after intravenous iron oxide administration have not been reported thus far. In this study, we investigated, if intravenously administered ferumoxytol nanoparticles are deposited in porcine brains. In an animal care and use committee-approved prospective case-control study, ten Göttingen minipigs received either intravenous ferumoxytol injections at a dose of 5 mg Fe/kg (n=4) or remained untreated (n=6). Nine to twelve months later, pigs were sacrificed and the brains of all pigs underwent MRI at 7T with T2 and T2*-weighted sequences. MRI scans were evaluated by measuring R2* values (R2*=1000/T2*) of the bilateral caudate nucleus, lentiform nucleus, thalamus, dentate nucleus, and choroid plexus. Pig brains were sectioned and stained with Prussian blue and evaluated for iron deposition using a semiquantitative scoring system. Data of ferumoxytol exposed and unexposed groups were compared with an unpaired t-test and a Mann-Whitney U test. T2 and T2* signal of the different brain regions was not visually different between ferumoxytol exposed and unexposed controls. There were no significant differences in R2* values of the different brain regions in the ferumoxytol exposed group compared to controls (p>0.05). Prussian blue stains of the same brain regions, scored according to a semiquantitative score, were not significantly different either between the ferumoxytol exposed group and unexposed controls (p>0.05). Our study shows that intravenous ferumoxytol doses of 5-10 mg Fe/kg do not lead to iron deposition in the brain of pigs. We suggest iron oxide nanoparticles as a promising alternative for gadolinium-enhanced MRI.
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http://dx.doi.org/10.7150/ntno.46356DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7332795PMC
April 2021

Papillary Thyroid Carcinoma in Struma Ovarii.

Cureus 2020 Apr 7;12(4):e7582. Epub 2020 Apr 7.

Pathology, Rutgers Robert Wood Johnson Medical School, New Brunswick, USA.

Struma ovarii is a variant of a germ cell tumor composed predominantly of thyroid tissue. It is most often unilateral. The incidence of malignancy arising in patients with struma ovarii is rare. Here, we present a case of struma ovarii in a female presented with abdominal distension. The patient was treated with a total hysterectomy and bilateral salpingo-oophorectomy, which revealed an enlarged cystically dilated ovary. Histopathologic examination showed mature thyroid follicles with abundant colloid consistent with struma ovarii and focal area with nuclear features of papillary thyroid carcinoma. No other teratomatous elements were identified. Thyroid hormone levels were within their respective reference ranges. A diagnosis of struma ovarii should be considered in the differential diagnosis of pelvic masses in peri- and postmenopausal patients.
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http://dx.doi.org/10.7759/cureus.7582DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7205381PMC
April 2020

Pigs in a blanket: an unusual presentation of malignant ascites in prostatic adenocarcinoma.

BMJ Case Rep 2019 Nov 14;12(11). Epub 2019 Nov 14.

Pathology, Buffalo VA Medical Center, Buffalo, New York, USA.

Malignant ascites in prostatic acinar adenocarcinoma is very rare. We present an 84-year-old man with a rare malignant ascites due to prostatic adenocarcinoma demonstrating hepatoid differentiation by immunohistochemistry. The patient was diagnosed with the malignant ascites due to metastatic prostatic adenocarcinoma. We identified the unique cytological feature of envelopment of tumour cell clusters by benign mesothelial monolayers.
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http://dx.doi.org/10.1136/bcr-2019-230899DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6887432PMC
November 2019

Theranostic nanoparticles enhance the response of glioblastomas to radiation.

Nanotheranostics 2019 17;3(4):299-310. Epub 2019 Sep 17.

Department of Radiology, Molecular Imaging Program at Stanford, Stanford University, Stanford, CA, USA.

Despite considerable progress with our understanding of glioblastoma multiforme (GBM) and the precise delivery of radiotherapy, the prognosis for GBM patients is still unfavorable with tumor recurrence due to radioresistance being a major concern. We recently developed a cross-linked iron oxide nanoparticle conjugated to azademethylcolchicine (CLIO-ICT) to target and eradicate a subpopulation of quiescent cells, glioblastoma initiating cells (GICs), which could be a reason for radioresistance and tumor relapse. The purpose of our study was to investigate if CLIO-ICT has an additive therapeutic effect to enhance the response of GBMs to ionizing radiation. NSG™ mice bearing human GBMs and C57BL/6J mice bearing murine GBMs received CLIO-ICT, radiation, or combination treatment. The mice underwent pre- and post-treatment magnetic resonance imaging (MRI) scans, bioluminescence imaging (BLI), and histological analysis. Tumor nanoparticle enhancement, tumor flux, microvessel density, GIC, and apoptosis markers were compared between different groups using a one-way ANOVA and two-tailed Mann-Whitney test. Additional NSG™ mice underwent survival analyses with Kaplan-Meier curves and a log rank (Mantel-Cox) test. At 2 weeks post-treatment, BLI and MRI scans revealed significant reduction in tumor size for CLIO-ICT plus radiation treated tumors compared to monotherapy or vehicle-treated tumors. Combining CLIO-ICT with radiation therapy significantly decreased microvessel density, decreased GICs, increased caspase-3 expression, and prolonged the survival of GBM-bearing mice. CLIO-ICT delivery to GBM could be monitored with MRI. and was not significantly different before and after radiation. There was no significant caspase-3 expression in normal brain at therapeutic doses of CLIO-ICT administered. Our data shows additive anti-tumor effects of CLIO-ICT nanoparticles in combination with radiotherapy. The combination therapy proposed here could potentially be a clinically translatable strategy for treating GBMs.
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http://dx.doi.org/10.7150/ntno.35342DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6838141PMC
June 2020

Improving the efficacy of osteosarcoma therapy: combining drugs that turn cancer cell 'don't eat me' signals off and 'eat me' signals on.

Mol Oncol 2019 10 13;13(10):2049-2061. Epub 2019 Aug 13.

Department of Radiology, Molecular Imaging Program at Stanford, Stanford University, CA, USA.

The long-term survival of osteosarcoma patients with metastatic or recurrent disease remains dismal, and new therapeutic options are urgently needed. The purpose of our study was to compare the efficacy of CD47 mAb plus doxorubicin combination therapy in mouse models of osteosarcoma with CD47 mAb and doxorubicin monotherapy. Forty-eight NOD scid gamma (NSG) mice with intratibial MNNG/HOS tumors received CD47 mAb, doxorubicin, combination therapy, or control IgG treatment. Twenty-four mice (n = 6 per group) underwent pre- and post-treatment magnetic resonance imaging (MRI) scans with the macrophage marker ferumoxytol, bioluminescence imaging, and histological analysis. Tumor ferumoxytol enhancement, tumor flux, and tumor-associated macrophages (TAM) density were compared between different groups using a one-way ANOVA. Twenty-four additional NSG mice underwent survival analyses with Kaplan-Meier curves and a log-rank (Mantel-Cox) test. Intratibial osteosarcomas demonstrated significantly stronger ferumoxytol enhancement and significantly increased TAM quantities after CD47 mAb plus doxorubicin combination therapy compared to CD47 mAb (P = 0.02) and doxorubicin monotherapy (P = 0.001). Tumor-bearing mice treated with CD47 mAb plus doxorubicin combination therapy demonstrated significantly reduced tumor size and prolonged survival compared to control groups that received CD47 mAb (P = 0.03), doxorubicin monotherapy (P = 0.01), and control IgG (P = 0.001). In conclusion, CD47 mAb plus doxorubicin therapy demonstrates an additive therapeutic effect in mouse models of osteosarcomas, which can be monitored with an immediately clinically applicable MRI technique.
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http://dx.doi.org/10.1002/1878-0261.12556DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6763764PMC
October 2019

Magnetic Resonance Imaging of Tumor-Associated Macrophages: Clinical Translation.

Clin Cancer Res 2018 09 15;24(17):4110-4118. Epub 2018 May 15.

Department of Radiology and Molecular Imaging Program at Stanford (MIPS), Stanford University, Stanford, California.

Tumor-associated macrophages (TAMs) in malignant tumors have been linked to tumor aggressiveness and represent a new target for cancer immunotherapy. As new TAM-targeted immunotherapies are entering clinical trials, it is important to detect and quantify TAM with noninvasive imaging techniques. The purpose of this study was to determine if ferumoxytol-enhanced MRI can detect TAM in lymphomas and bone sarcomas of pediatric patients and young adults. In a , Institutional Review Board-approved prospective clinical trial, 25 pediatric and young adult patients with lymphoma or bone sarcoma underwent ferumoxytol-enhanced MRI. To confirm ferumoxytol enhancement, five pilot patients (two lymphoma and three bone sarcoma) underwent pre- and postcontrast MRI. Subsequently, 20 patients (10 lymphoma and 10 bone sarcoma) underwent ferumoxytol-enhanced MRI 24 to 48 hours after i.v. injection, followed by tumor biopsy/resection and macrophage staining. To determine if ferumoxytol-MRI can differentiate tumors with different TAM content, we compared T2* relaxation times of lymphomas and bone sarcomas. Tumor T2* values of 20 patients were correlated with CD68 and CD163 TAM quantities on histopathology. Significant ferumoxytol tumor enhancement was noted on postcontrast scans compared with precontrast scans ( = 0.036). Bone sarcomas and lymphomas demonstrated significantly different MRI enhancement and TAM density ( < 0.05). Within each tumor group, T2* signal enhancement on MR images correlated significantly with the density of CD68 and CD163 TAM ( < 0.05). Ferumoxytol-enhanced MRI is immediately clinically applicable and could be used to stratify patients with TAM-rich tumors to immune-targeted therapies and to monitor tumor response to these therapies. .
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http://dx.doi.org/10.1158/1078-0432.CCR-18-0673DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6125171PMC
September 2018

How to Provide Gadolinium-Free PET/MR Cancer Staging of Children and Young Adults in Less than 1 h: the Stanford Approach.

Mol Imaging Biol 2018 04;20(2):324-335

Department of Radiology, Pediatric Radiology, Lucile Packard Children's Hospital, Stanford University, 725 Welch Rd, Stanford, CA, 94305-5654, USA.

Purpose: To provide clinically useful gadolinium-free whole-body cancer staging of children and young adults with integrated positron emission tomography/magnetic resonance (PET/MR) imaging in less than 1 h.

Procedures: In this prospective clinical trial, 20 children and young adults (11-30 years old, 6 male, 14 female) with solid tumors underwent 2-deoxy-2-[F]fluoro-D-glucose ([F]FDG) PET/MR on a 3T PET/MR scanner after intravenous injection of ferumoxytol (5 mg Fe/kg) and [F]FDG (2-3 MBq/kg). Time needed for patient preparation, PET/MR image acquisition, and data processing was compared before (n = 5) and after (n = 15) time-saving interventions, using a Wilcoxon test. The ferumoxytol-enhanced PET/MR images were compared with clinical standard staging tests regarding radiation exposure and tumor staging results, using Fisher's exact tests.

Results: Tailored workflows significantly reduced scan times from 36 to 24 min for head to mid thigh scans (p < 0.001). These streamlined PET/MR scans were obtained with significantly reduced radiation exposure (mean 3.4 mSv) compared to PET/CT with diagnostic CT (mean 13.1 mSv; p = 0.003). Using the iron supplement ferumoxytol "off label" as an MR contrast agent avoided gadolinium chelate administration. The ferumoxytol-enhanced PET/MR scans provided equal or superior tumor staging results compared to clinical standard tests in 17 out of 20 patients. Compared to PET/CT, PET/MR had comparable detection rates for pulmonary nodules with diameters of equal or greater than 5 mm (94 vs. 100 %), yet detected significantly fewer nodules with diameters of less than 5 mm (20 vs 100 %) (p = 0.03). [F]FDG-avid nodules were detected with slightly higher sensitivity on the PET of the PET/MR compared to the PET of the PET/CT (59 vs 49 %).

Conclusion: Our streamlined ferumoxytol-enhanced PET/MR protocol provided cancer staging of children and young adults in less than 1 h with equivalent or superior clinical information compared to clinical standard staging tests. The detection of small pulmonary nodules with PET/MR needs to be improved.
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http://dx.doi.org/10.1007/s11307-017-1105-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5773418PMC
April 2018

Ferumoxytol Is Not Retained in Kidney Allografts in Patients Undergoing Acute Rejection.

Mol Imaging Biol 2018 02;20(1):139-149

Department of Radiology, Pediatric Molecular Imaging in the Molecular Imaging Program at Stanford (@PedsMIPS), Lucile Packard Children's Hospital, Stanford University School of Medicine, 725 Welch Road, Stanford, 94305, CA, USA.

Purpose: To evaluate whether ultrasmall superparamagnetic iron oxide nanoparticle (USPIO)-enhanced magnetic resonance imaging (MRI) can detect allograft rejection in pediatric kidney transplant patients.

Procedures: The USPIO ferumoxytol has a long blood half-life and is phagocytosed by macrophages. In an IRB-approved single-center prospective clinical trial, 26 pediatric patients and adolescents (age 10-26 years) with acute allograft rejection (n = 5), non-rejecting allografts (n = 13), and normal native kidneys (n = 8) underwent multi-echo T2* fast spoiled gradient-echo (FSPGR) MRI after intravenous injection (p.i.) of 5 mg Fe/kg ferumoxytol. T2* relaxation times at 4 h p.i. (perfusion phase) and more than 20 h p.i. (macrophage phase) were compared with biopsy results. The presence of rejection was assessed using the Banff criteria, and the prevalence of macrophages on CD163 immunostains was determined based on a semi-quantitative scoring system. MRI and histology data were compared among patient groups using t tests, analysis of variance, and regression analyses with a significance threshold of p < 0.05.

Results: At 4 h p.i., mean T2* values were 6.6 ± 1.5 ms for native kidneys and 3.9 ms for one allograft undergoing acute immune rejection. Surprisingly, at 20-24 h p.i., one rejecting allograft showed significantly prolonged T2* relaxation times (37.0 ms) compared to native kidneys (6.3 ± 1.7 ms) and non-rejecting allografts (7.6 ± 0.1 ms). Likewise, three additional rejecting allografts showed significantly prolonged T2* relaxation times compared to non-rejecting allografts at later post-contrast time points, 25-97 h p.i. (p = 0.008). Histological analysis revealed edema and compressed microvessels in biopsies of rejecting allografts. Allografts with and without rejection showed insignificant differences in macrophage content on histopathology (p = 0.44).

Conclusion: After ferumoxytol administration, renal allografts undergoing acute rejection show prolonged T2* values compared to non-rejecting allografts. Since histology revealed no significant differences in macrophage content, the increasing T2* value is likely due to the combined effect of reduced perfusion and increased edema in rejecting allografts.
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http://dx.doi.org/10.1007/s11307-017-1084-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6391060PMC
February 2018

Speeding up PET/MR for cancer staging of children and young adults.

Eur Radiol 2016 Dec 5;26(12):4239-4248. Epub 2016 Apr 5.

Department of Radiology, Molecular Imaging Program at Stanford, Stanford University, 725 Welch Road, Stanford, CA, 94304, USA.

Objective: Combining F-FDG PET with whole-body MR for paediatric cancer staging is practically feasible if imaging protocols can be streamlined. We compared F-FDG PET/STIR with accelerated F-FDG PET/FSPGR for whole-body tumour imaging in children and young adults.

Methods: Thirty-three children and young adults (17.5 ± 5.5 years, range 10-30) with malignant lymphoma or sarcoma underwent a F-FDG PET staging examination, followed by ferumoxytol-enhanced STIR and FSPGR whole-body MR. F-FDG PET scans were fused with MR data and the number and location of tumours on each integrated examination were determined. Histopathology and follow-up imaging served as standard of reference. The agreement of each MR sequence with the reference and whole-body imaging times were compared using Cohen's kappa coefficient and Student's t-test, respectively.

Results: Comparing F-FDG PET/FSPGR to F-FDG PET/STIR, sensitivities were 99.3 % for both, specificities were statistically equivalent, 99.8 versus 99.9 %, and the agreement with the reference based on Cohen's kappa coefficient was also statistically equivalent, 0.989 versus 0.992. However, the total scan-time for accelerated FSPGR of 19.8 ± 5.3 minutes was significantly shorter compared to 29.0 ± 7.6 minutes for STIR (p = 0.001).

Conclusion: F-FDG PET/FSPGR demonstrated equivalent sensitivities and specificities for cancer staging compared to F-FDG PET/STIR, but could be acquired with shorter acquisition time.

Key Points: • Breath-hold FSPGR sequences shorten the data acquisition time for whole-body MR and PET/MR. • Ferumoxytol provides long-lasting vascular contrast for whole-body MR and PET/MR. • F-FDG PET/FSPGR data provided equal sensitivity and specificity for cancer staging compared to F-FDG PET/STIR.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5052123PMC
http://dx.doi.org/10.1007/s00330-016-4332-4DOI Listing
December 2016

Three-dimensional Radiologic Assessment of Chemotherapy Response in Ewing Sarcoma Can Be Used to Predict Clinical Outcome.

Radiology 2016 09 16;280(3):905-15. Epub 2016 Mar 16.

From the Department of Radiology, Section of Pediatric Radiology (M.A., J.B., J.R., R.S.G., T.K.S., H.E.D.L.), and Department of Pediatric Hematology/Oncology (N.M.M.), Lucile Packard Children's Hospital, Stanford University, 725 Welch Rd, Stanford, CA 94305-5654; Department of Radiation and Oncology, Stanford University, Stanford, Calif (R.V.E.); Department of Pediatric and Prenatal Imaging, Hôpital de la Timone, Marseille, France (P.P.); Department of Pediatrics, University of California-San Francisco School of Medicine, San Francisco, Calif (J.S., S.G.D.); and UCSF Benioff Children's Hospital, San Francisco, Calif (J.S., S.G.D.).

Purpose To compare the agreement of three-dimensional (3D) tumor measurements for therapeutic response assessment of Ewing sarcoma according to the Children's Oncology Group (COG) criteria, one-dimensional (1D) Response Evaluation Criteria in Solid Tumors (RECIST), and two-dimensional (2D) measurements defined by the World Health Organization (WHO) with tumor volume measurements as the standard of reference and to determine which method correlates best with clinical outcomes. Materials and Methods This retrospective study was approved by the institutional review board of three institutions. Seventy-four patients (mean age ± standard deviation, 14.5 years ± 6.5) with newly diagnosed Ewing sarcoma treated at three medical centers were evaluated. Primary tumor size was assessed on pre- and posttreatment magnetic resonance images according to 1D RECIST, 2D WHO, and 3D COG measurements. Tumor responses were compared with the standard of reference (tumor volume) on the basis of RECIST, COG, and WHO therapeutic response thresholds. Agreement between the percentage reduction measurements of the methods was assessed with concordance correlation, Bland-Altman analysis, and Spearman rank correlation. Agreement between therapeutic responses was assessed with Kendall tau and unweighted κ statistics. Tumor responses were compared with patient survival by using the log-rank test, Kaplan-Meier plots, and Cox regression. Results Agreement with the reference standard was significantly better for 3D measurement than for 1D and 2D measurements on the basis of RECIST and COG therapeutic response thresholds (concordance correlation of 0.41, 0.72, and 0.84 for 1D, 2D, and 3D measurements, respectively; P < .0001). Comparison of overall survival of responders and nonresponders demonstrated P values of .4133, .0112, .0032, and .0027 for 1D, 2D, 3D, and volume measurements, respectively, indicating that higher dimensional measurements were significantly better predictors of overall survival. Conclusion The 3D tumor measurements according to COG are better predictors of therapeutic response of Ewing sarcoma than 1D RECIST or 2D WHO measurements and show a significantly higher correlation with clinical outcomes. (©) RSNA, 2016 Online supplemental material is available for this article.
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http://dx.doi.org/10.1148/radiol.2016151301DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5006736PMC
September 2016

Imaging Tumor Necrosis with Ferumoxytol.

PLoS One 2015 16;10(11):e0142665. Epub 2015 Nov 16.

Department of Radiology, Molecular Imaging Program at Stanford, Stanford University, Stanford, CA, United States of America.

Objective: Ultra-small superparamagnetic iron oxide nanoparticles (USPIO) are promising contrast agents for magnetic resonance imaging (MRI). USPIO mediated proton relaxation rate enhancement is strongly dependent on compartmentalization of the agent and can vary depending on their intracellular or extracellular location in the tumor microenvironment. We compared the T1- and T2-enhancement pattern of intracellular and extracellular USPIO in mouse models of cancer and pilot data from patients. A better understanding of these MR signal effects will enable non-invasive characterizations of the composition of the tumor microenvironment.

Materials And Methods: Six 4T1 and six MMTV-PyMT mammary tumors were grown in mice and imaged with ferumoxytol-enhanced MRI. R1 relaxation rates were calculated for different tumor types and different tumor areas and compared with histology. The transendothelial leakage rate of ferumoxytol was obtained by our measured relaxivity of ferumoxytol and compared between different tumor types, using a t-test. Additionally, 3 patients with malignant sarcomas were imaged with ferumoxytol-enhanced MRI. T1- and T2-enhancement patterns were compared with histopathology in a descriptive manner as a proof of concept for clinical translation of our observations.

Results: 4T1 tumors showed central areas of high signal on T1 and low signal on T2 weighted MR images, which corresponded to extracellular nanoparticles in a necrotic core on histopathology. MMTV-PyMT tumors showed little change on T1 but decreased signal on T2 weighted images, which correlated to compartmentalized nanoparticles in tumor associated macrophages. Only 4T1 tumors demonstrated significantly increased R1 relaxation rates of the tumor core compared to the tumor periphery (p<0.001). Transendothelial USPIO leakage was significantly higher for 4T1 tumors (3.4±0.9x10-3 mL/min/100cm3) compared to MMTV-PyMT tumors (1.0±0.9x10-3 mL/min/100 cm3). Likewise, ferumoxytol imaging in patients showed similar findings with high T1 signal in areas of tumor necrosis and low signal in areas of intracellularly compartmentalized iron.

Conclusion: Differential T1- and T2-enhancement patterns of USPIO in tumors enable conclusions about their intracellular and extracellular location. This information can be used to characterize the composition of the tumor microenvironment.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0142665PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4646285PMC
June 2016