Publications by authors named "Ronald L Korn"

27 Publications

  • Page 1 of 1

Intratumoral Injection of -NT Spores in Patients with Treatment-refractory Advanced Solid Tumors.

Clin Cancer Res 2021 Jan 12;27(1):96-106. Epub 2020 Oct 12.

BioMed Valley Discoveries Inc., Kansas City, Missouri.

Purpose: Intratumorally injected -NT (nontoxic; lacking the alpha toxin), an attenuated strain of , replicates within hypoxic tumor regions resulting in tumor-confined cell lysis and inflammatory response in animals, which warrants clinical investigation.

Patients And Methods: This first-in-human study (NCT01924689) enrolled patients with injectable, treatment-refractory solid tumors to receive a single intratumoral injection of -NT across 6 dose cohorts (1 × 10 to 3 × 10 spores, 3+3 dose-escalation design) to determine dose-limiting toxicities (DLT), and the maximum tolerated dose.

Results: Among 24 patients, a single intratumoral injection of -NT led to bacterial spores germination and the resultant lysis of injected tumor masses in 10 patients (42%) across all doses. The cohort 5 dose (1 × 10 spores) was defined as the maximum tolerated dose; DLTs were grade 4 sepsis ( = 2) and grade 4 gas gangrene ( = 1), all occurring in three patients with injected tumors >8 cm. Other treatment-related grade ≥3 toxicities included pathologic fracture ( = 1), limb abscess ( = 1), soft-tissue infection ( = 1), respiratory insufficiency ( = 1), and rash ( = 1), which occurred across four patients. Of 22 evaluable patients, nine (41%) had a decrease in size of the injected tumor and 19 (86%) had stable disease as the best overall response in injected and noninjected lesions combined. -NT injection elicited a transient systemic cytokine response and enhanced systemic tumor-specific T-cell responses.

Conclusions: Single intratumoral injection of NT is feasible. Toxicities can be significant but manageable. Signals of antitumor activity and the host immune response support additional studies of NT in humans.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-2065DOI Listing
January 2021

Dose-response assessment by quantitative MRI in a phase 1 clinical study of the anti-cancer vascular disrupting agent crolibulin.

Sci Rep 2020 09 2;10(1):14449. Epub 2020 Sep 2.

Department of Cancer Physiology, Moffitt Cancer Center, SRB-4, Tampa, FL, 33612, USA.

The vascular disrupting agent crolibulin binds to the colchicine binding site and produces anti-vascular and apoptotic effects. In a multisite phase 1 clinical study of crolibulin (NCT00423410), we measured treatment-induced changes in tumor perfusion and water diffusivity (ADC) using dynamic contrast-enhanced MRI (DCE-MRI) and diffusion-weighted MRI (DW-MRI), and computed correlates of crolibulin pharmacokinetics. 11 subjects with advanced solid tumors were imaged by MRI at baseline and 2-3 days post-crolibulin (13-24 mg/m). ADC maps were computed from DW-MRI. Pre-contrast T maps were computed, co-registered with the DCE-MRI series, and maps of area-under-the-gadolinium-concentration-curve-at-90 s (AUC) and the Extended Tofts Model parameters k, v, and v were calculated. There was a strong correlation between higher plasma drug [Formula: see text] and a linear combination of (1) reduction in tumor fraction with [Formula: see text] mM s, and, (2) increase in tumor fraction with [Formula: see text]. A higher plasma drug AUC was correlated with a linear combination of (1) increase in tumor fraction with [Formula: see text], and, (2) increase in tumor fraction with [Formula: see text]. These findings are suggestive of cell swelling and decreased tumor perfusion 2-3 days post-treatment with crolibulin. The multivariable linear regression models reported here can inform crolibulin dosing in future clinical studies of crolibulin combined with cytotoxic or immune-oncology agents.
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http://dx.doi.org/10.1038/s41598-020-71246-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7468301PMC
September 2020

Use of Precision Imaging in the Evaluation of Pancreas Cancer.

Cancer Treat Res 2019 ;178:209-236

Virginia G Piper Cancer Center at HonorHealth, Scottsdale, AZ, USA.

Pancreas cancer is an aggressive and fatal disease that will become one of the leading causes of cancer mortality by 2030. An all-out effort is underway to better understand the basic biologic mechanisms of this disease ranging from early development to metastatic disease. In order to change the course of this disease, diagnostic radiology imaging may play a vital role in providing a precise, noninvasive method for early diagnosis and assessment of treatment response. Recent progress in combining medical imaging, advanced image analysis and artificial intelligence, termed radiomics, can offer an innovate approach in detecting the earliest changes of tumor development as well as a rapid method for the detection of response. In this chapter, we introduce the principles of radiomics and demonstrate how it can provide additional information into tumor biology, early detection, and response assessments advancing the goals of precision imaging to deliver the right treatment to the right person at the right time.
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http://dx.doi.org/10.1007/978-3-030-16391-4_8DOI Listing
June 2019

E6201, an intravenous MEK1 inhibitor, achieves an exceptional response in BRAF V600E-mutated metastatic malignant melanoma with brain metastases.

Invest New Drugs 2019 08 28;37(4):636-645. Epub 2018 Sep 28.

Honor Health Research Institute, 10510 N. 92nd Street, #200, Scottsdale, AZ, 85258, USA.

Malignant melanoma (MM) exhibits a high propensity for central nervous system dissemination with ~50% of metastatic MM patients developing brain metastases (BM). Targeted therapies and immune checkpoint inhibitors have improved overall survival for MM patients with BM. However, responses are usually of short duration and new agents that effectively penetrate the blood brain barrier (BBB) are needed. Here, we report a MM patient with BM who experienced an exceptional response to E6201, an ATP-competitive MEK1 inhibitor, on a Phase 1 study, with ongoing near-complete response and overall survival extending beyond 8 years. Whole exome and transcriptome sequencing revealed a high mutational burden tumor (22 mutations/Megabase) with homozygous BRAF V600E mutation. Correlative preclinical studies demonstrated broad activity for E6201 across BRAF V600E mutant melanoma cell lines and effective BBB penetration in vivo. Together, these results suggest that E6201 may represent a potential new treatment option for BRAF-mutant MM patients with BM.
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http://dx.doi.org/10.1007/s10637-018-0668-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7519637PMC
August 2019

Magnetic resonance imaging of RRx-001 pharmacodynamics in preclinical tumors.

Oncotarget 2017 Nov 12;8(60):102511-102520. Epub 2017 Jun 12.

Imaging Endpoints LLC, Scottsdale, Arizona, USA.

RRx-001 is an anticancer agent that subjects cancer cells to reactive oxygen/nitrogen species (ROS/RNS) and acts as an epigenetic modifier. We have used a thiol-bearing MRI contrast agent, Gd-LC7-SH, to investigate the pharmacodynamics of RRx-001 in CHP-100 Ewing's Sarcoma, HT-29 colorectal carcinoma, and PANC-1 pancreatic carcinoma xenografts in SCID mice. Binding of Gd-LC7-SH to the Cys residue on plasma albumin prolongs retention in the tumor microenvironment and increases tumor enhancement on MRI. Mice were imaged by MRI and T1 maps acquired 50 min (T1) after injection of 0.05 mmol/kg Gd-LC7-SH (i.v.) at baseline and 1, 24, and 72 h post-treatment with 10 mg/kg RRx-001 (i.v.). Consistent with an indirect thiol-modifying activity of RRx-001, tumor T1 at 1 h post-drug was significantly longer than pre-drug tumor T1 in all three tumor models, with the T1 remaining significantly longer than baseline through 72 h post-drug in the HT-29 and PANC-1 tumors. The T1 of CHP-100 tumors recovered to baseline by 24 h post-drug, suggesting a robust anti-oxidant response to the RRx-001 challenge that was presaged by a marked increase in perfusion at 1 h post-drug measured by DCE-MRI. MRI enhanced with Gd-LC7-SH provides a mechanistically rational biomarker of RRx-001 pharmacodynamics.
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http://dx.doi.org/10.18632/oncotarget.18455DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5731976PMC
November 2017

Phase 1 trials of PEGylated recombinant human hyaluronidase PH20 in patients with advanced solid tumours.

Br J Cancer 2018 01 26;118(2):153-161. Epub 2017 Sep 26.

Mayo Clinic, 13400 E. Shea Boulevard, Scottsdale, AZ 85259, USA.

Background: Hyaluronan accumulation in tumour stroma is associated with reduced survival in preclinical cancer models. PEGPH20 degrades hyaluronan to facilitate tumour access for cancer therapies. Our objective was to assess safety and antitumour activity of PEGPH20 in patients with advanced solid tumours.

Methods: In HALO-109-101 (N=14), PEGPH20 was administered intravenously once or twice weekly (0.5 or 50 μg kg) or once every 3 weeks (0.5-1.5 μg kg). In HALO-109-102 (N=27), PEGPH20 was administered once or twice weekly (0.5-5.0 μg kg), with dexamethasone predose and postdose.

Results: Dose-limiting toxicities included grade ⩾3 myalgia, arthralgia, and muscle spasms; the maximum tolerated dose was 3.0 μg kg twice weekly. Plasma hyaluronan increased in a dose-dependent manner, achieving steady state by Day 8 in multidose studies. A decrease in tumour hyaluronan level was observed in 5 of the 6 patients with pretreatment and posttreatment tumour biopsies. Exploratory imaging showed changes in tumour perfusion and decreased tumour metabolic activity, consistent with observations in animal models.

Conclusions: The tumour stroma has emerging importance in the development of cancer therapeutics. PEGPH20 3.0 μg kg administered twice weekly is feasible in patients with advanced cancers; exploratory analyses indicate antitumour activity supporting further evaluation of PEGPH20 in solid tumours.
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http://dx.doi.org/10.1038/bjc.2017.327DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5785735PMC
January 2018

F-FDG PET/CT response in a phase 1/2 trial of nab-paclitaxel plus gemcitabine for advanced pancreatic cancer.

Cancer Imaging 2017 Aug 3;17(1):23. Epub 2017 Aug 3.

Mayo Clinic, 13400 E Shea Blvd, Scottsdale, AZ, 85259, USA.

Background: Positron emission tomography (PET) is poised to become a useful imaging modality in staging and evaluating therapeutic responses in patients with metastatic pancreatic cancer (mPC). This analysis from a phase 1/2 study examined the utility of early PET imaging in patients with mPC treated with nab-paclitaxel plus gemcitabine.

Methods: Tumors were measured by [F]2-fluoro-2-deoxyglucose PET/computed tomography (CT) in patients who received nab-paclitaxel 100 (n = 13), 125 (n = 38), or 150 (n = 1) mg/m plus gemcitabine 1000 mg/m on days 1, 8, and 15 of a 28-day cycle. Lesion metabolic activity was evaluated at baseline and 6 and 12 weeks postbaseline.

Results: Fifty-two patients had baseline and ≥1 follow-up PET scan. The median maximum standardized uptake values per pancreatic lesion in the nab-paclitaxel 100 mg/m and 125 mg/m cohorts were 5.1 and 6.5, respectively. Among patients who had a metabolic response by PET, those who received nab-paclitaxel 125 mg/m had a 4-month survival advantage over those who received 100 mg/m. All patients in the nab-paclitaxel 125 mg/m cohort experienced an early complete metabolic response (CMR; 34%) or partial metabolic response (PMR; 66%). In the nab-paclitaxel 125 mg/m cohort, investigator-assessed objective response rates were 77% and 44% among patients with a CMR and PMR, respectively, with no correlation between PET and CT response (Spearman r  = 0.22; P = 0.193). Patients in the nab-paclitaxel 125 mg/m cohort with a CMR experienced a significantly longer overall survival vs those with a PMR (median, 23.0 vs 11.2 months; P = 0.011), and a significant correlation was found between best percentage change in tumor burden by PET and survival: for each 1% decrease in PET score, the risk of death decreased by 2%.

Conclusions: The majority of primary pancreatic tumors and their metastases were PET avid, and PET effectively measured changes in tumor metabolic activity at 6 and 12 weeks. These results support the antitumor activity of nab-paclitaxel 125 mg/m plus gemcitabine 1000 mg/m for treating mPC and the utility of PET for measuring treatment response. Treatment response by PET analysis may be considered when evaluating investigational agents in mPC.

Trial Registration: NCT00398086.
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http://dx.doi.org/10.1186/s40644-017-0125-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5543580PMC
August 2017

Correlation between Ferumoxytol Uptake in Tumor Lesions by MRI and Response to Nanoliposomal Irinotecan in Patients with Advanced Solid Tumors: A Pilot Study.

Clin Cancer Res 2017 Jul 3;23(14):3638-3648. Epub 2017 Feb 3.

Merrimack Pharmaceuticals, Inc., Cambridge, Massachusetts.

To determine whether deposition characteristics of ferumoxytol (FMX) iron nanoparticles in tumors, identified by quantitative MRI, may predict tumor lesion response to nanoliposomal irinotecan (nal-IRI). Eligible patients with previously treated solid tumors had FMX-MRI scans before and following (1, 24, and 72 hours) FMX injection. After MRI acquisition, R2* signal was used to calculate FMX levels in plasma, reference tissue, and tumor lesions by comparison with a phantom-based standard curve. Patients then received nal-IRI (70 mg/m free base strength) biweekly until progression. Two percutaneous core biopsies were collected from selected tumor lesions 72 hours after FMX or nal-IRI. Iron particle levels were quantified by FMX-MRI in plasma, reference tissues, and tumor lesions in 13 of 15 eligible patients. On the basis of a mechanistic pharmacokinetic model, tissue permeability to FMX correlated with early FMX-MRI signals at 1 and 24 hours, while FMX tissue binding contributed at 72 hours. Higher FMX levels (ranked relative to median value of multiple evaluable lesions from 9 patients) were significantly associated with reduction in lesion size by RECIST v1.1 at early time points ( < 0.001 at 1 hour and < 0.003 at 24 hours FMX-MRI, one-way ANOVA). No association was observed with post-FMX levels at 72 hours. Irinotecan drug levels in lesions correlated with patient's time on treatment (Spearman = 0.7824; = 0.0016). Correlation between FMX levels in tumor lesions and nal-IRI activity suggests that lesion permeability to FMX and subsequent tumor uptake may be a useful noninvasive and predictive biomarker for nal-IRI response in patients with solid tumors. .
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http://dx.doi.org/10.1158/1078-0432.CCR-16-1990DOI Listing
July 2017

Radiogenomic Analysis Demonstrates Associations between (18)F-Fluoro-2-Deoxyglucose PET, Prognosis, and Epithelial-Mesenchymal Transition in Non-Small Cell Lung Cancer.

Radiology 2016 07 15;280(1):261-70. Epub 2016 Apr 15.

From the Department of Radiology, The David Geffen School of Medicine at University of California-Los Angeles (UCLA), 10833 LeConte Ave, Box 951721, CHS 17-135, Los Angeles, CA 90095-1721 (S.Y., D.H., L.D., N.J., B.L.B., M.D.K.); Department of Bioengineering, UCLA, Los Angeles, Calif (M.D.K.); and Scottsdale Medical Imaging, Scottsdale, Ariz (R.L.K.).

Purpose To investigate whether non-small cell lung cancer (NSCLC) tumors that express high normalized maximum standardized uptake value (SUVmax) are associated with a more epithelial-mesenchymal transition (EMT)-like phenotype. Materials and Methods In this institutional review board-approved study, a public NSCLC data set that contained fluorine 18 ((18)F) fluoro-2-deoxyglucose positron emission tomography (PET) and messenger RNA expression profile data (n = 26) was obtained, and patients were categorized on the basis of measured normalized SUVmax values. Significance analysis of microarrays was then used to create a radiogenomic signature. The prognostic ability of this signature was assessed in a second independent data set that consisted of clinical and messenger RNA expression data (n = 166). Signature concordance with EMT was evaluated by means of validation in a publicly available cell line data set. Finally, by establishing an in vitro EMT lung cancer cell line model, an attempt was made to substantiate the radiogenomic signature with quantitative polymerase chain reaction, and functional assays were performed, including Western blot, cell migration, glucose transporter, and hexokinase assays (paired t test), as well as pharmacologic assays against chemotherapeutic agents (half-maximal effective concentration). Results Differential expression analysis yielded a 14-gene radiogenomic signature (P < .05, false discovery rate [FDR] < 0.20), which was confirmed to have differences in disease-specific survival (log-rank test, P = .01). This signature also significantly overlapped with published EMT cell line gene expression data (P < .05, FDR < 0.20). Finally, an EMT cell line model was established, and cells that had undergone EMT differentially expressed this signature and had significantly different EMT protein expression (P < .05, FDR < 0.20), cell migration, glucose uptake, and hexokinase activity (paired t test, P < .05). Cells that had undergone EMT also had enhanced chemotherapeutic resistance, with a higher half-maximal effective concentration than that of cells that had not undergone EMT (P < .05). Conclusion Integrative radiogenomic analysis demonstrates an association between increased normalized (18)F fluoro-2-deoxyglucose PET SUVmax, outcome, and EMT in NSCLC. (©) RSNA, 2016 Online supplemental material is available for this article.
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http://dx.doi.org/10.1148/radiol.2016160259DOI Listing
July 2016

The radiogenomic risk score stratifies outcomes in a renal cell cancer phase 2 clinical trial.

Eur Radiol 2016 Aug 11;26(8):2798-807. Epub 2015 Nov 11.

Department of Radiological Sciences, University of California-Los Angeles, David Geffen School of Medicine, Los Angeles, CA, USA.

Objectives: To characterize a radiogenomic risk score (RRS), a previously defined biomarker, and to evaluate its potential for stratifying radiological progression-free survival (rPFS) in patients with metastatic renal cell carcinoma (mRCC) undergoing pre-surgical treatment with bevacizumab.

Methodology: In this IRB-approved study, prospective imaging analysis of the RRS was performed on phase II clinical trial data of mRCC patients (n = 41) evaluating whether patient stratification according to the RRS resulted in groups more or less likely to have a rPFS to pre-surgical bevacizumab prior to cytoreductive nephrectomy. Survival times of RRS subgroups were analyzed using Kaplan-Meier survival analysis.

Results: The RRS is enriched in diverse molecular processes including drug response, stress response, protein kinase regulation, and signal transduction pathways (P < 0.05). The RRS successfully stratified rPFS to bevacizumab based on pre-treatment computed tomography imaging with a median progression-free survival of 6 versus >25 months (P = 0.005) and overall survival of 25 versus >37 months in the high and low RRS groups (P = 0.03), respectively. Conventional prognostic predictors including the Motzer and Heng criteria were not predictive in this cohort (P > 0.05).

Conclusions: The RRS stratifies rPFS to bevacizumab in patients from a phase II clinical trial with mRCC undergoing cytoreductive nephrectomy and pre-surgical bevacizumab.

Key Points: • The RRS SOMA stratifies patient outcomes in a phase II clinical trial. • RRS stratifies subjects into prognostic groups in a discrete or continuous fashion. • RRS is biologically enriched in diverse processes including drug response programs.
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http://dx.doi.org/10.1007/s00330-015-4082-8DOI Listing
August 2016

The Radiogenomic Risk Score: Construction of a Prognostic Quantitative, Noninvasive Image-based Molecular Assay for Renal Cell Carcinoma.

Radiology 2015 Oct 19;277(1):114-23. Epub 2015 Aug 19.

From the Department of Radiological Sciences, David Geffen School of Medicine at UCLA, Box 951721, CHS 17-135, 10833 LeConte Ave, Los Angeles, CA 90095-1721 (N.J., M.Z., S.B., M.D.K.); Department of Genitourinary Medical Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, Tex (E.J.); Department of Radiology, Hospital of Veterans Affairs, University of California-San Diego, San Diego, Calif (M.Z., L.A.); Scottsdale Medical Imaging, Scottsdale, Ariz (R.K.); Department of Urology, Stanford University School of Medicine, Stanford, Calif (H.Z., J.D.B.); Department of Surgical and Perioperative Sciences, Urology and Andrology, Umea Hospital, Umea, Sweden (R.T.S., B.L.); and Department of Statistics, Stanford University, Stanford, Calif (R.J.T.).

Purpose: To evaluate the feasibility of constructing radiogenomic-based surrogates of molecular assays (SOMAs) in patients with clear-cell renal cell carcinoma (CCRCC) by using data extracted from a single computed tomographic (CT) image.

Materials And Methods: In this institutional review board approved study, gene expression profile data and contrast material-enhanced CT images from 70 patients with CCRCC in a training set were independently assessed by two radiologists for a set of predefined imaging features. A SOMA for a previously validated CCRCC-specific supervised principal component (SPC) risk score prognostic gene signature was constructed and termed the radiogenomic risk score (RRS). It uses the microarray data and a 28-trait image array to evaluate each CT image with multiple regression of gene expression analysis. The predictive power of the RRS SOMA was then prospectively validated in an independent dataset to confirm its relationship to the SPC gene signature (n = 70) and determination of patient outcome (n = 77). Data were analyzed by using multivariate linear regression-based methods and Cox regression modeling, and significance was assessed with receiver operator characteristic curves and Kaplan-Meier survival analysis.

Results: Our SOMA faithfully represents the tissue-based molecular assay it models. The RRS scaled with the SPC gene signature (R = 0.57, P < .001, classification accuracy 70.1%, P < .001) and predicted disease-specific survival (log rank P < .001). Independent validation confirmed the relationship between the RRS and the SPC gene signature (R = 0.45, P < .001, classification accuracy 68.6%, P < .001) and disease-specific survival (log-rank P < .001) and that it was independent of stage, grade, and performance status (multivariate Cox model P < .05, log-rank P < .001).

Conclusion: A SOMA for the CCRCC-specific SPC prognostic gene signature that is predictive of disease-specific survival and independent of stage was constructed and validated, confirming that SOMA construction is feasible.
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http://dx.doi.org/10.1148/radiol.2015150800DOI Listing
October 2015

(90)Y-clivatuzumab tetraxetan with or without low-dose gemcitabine: A phase Ib study in patients with metastatic pancreatic cancer after two or more prior therapies.

Eur J Cancer 2015 Sep 14;51(14):1857-64. Epub 2015 Jul 14.

Immunomedics, Inc., Morris Plains, NJ, United States; Center for Molecular Medicine and Immunology/Garden State Cancer Center, Morris Plains, NJ, United States. Electronic address:

Background: For patients with metastatic pancreatic adenocarcinoma, there are no approved or established treatments beyond the 2nd line. A Phase Ib study of fractionated radioimmunotherapy was undertaken in this setting, administering (90)Y-clivatuzumab tetraxetan (yttrium-90-radiolabelled humanised antibody targeting pancreatic adenocarcinoma mucin) with or without low radiosensitising doses of gemcitabine.

Methods: Fifty-eight patients with three (2-7) median prior treatments were treated on Arm A (N=29, (90)Y-clivatuzumab tetraxetan, weekly 6.5 mCi/m(2)doses×3, plus gemcitabine, weekly 200 mg/m(2) doses×4 starting 1 week earlier) or Arm B (N=29, (90)Y-clivatuzumab tetraxetan alone, weekly 6.5 mCi/m(2)doses×3), repeating cycles after 4-week delays. Safety was the primary endpoint; efficacy was also evaluated.

Results: Cytopaenias (predominantly transient thrombocytopenia) were the only significant toxicities. Fifty-three patients (27 Arm A, 26 Arm B, 91% overall) completed ⩾1 full treatment cycles, with 23 (12 Arm A, 11 Arm B; 40%) receiving multiple cycles, including seven (6 Arm A, 1 Arm B; 12%) given 3-9 cycles. Two patients in Arm A had partial responses by RECIST criteria. Kaplan-Meier overall survival (OS) appeared improved in Arm A versus B (hazard ratio [HR] 0.55, 95% CI: 0.29-0.86; P=0.017, log-rank) and the median OS for Arm A versus Arm B increased to 7.9 versus 3.4 months with multiple cycles (HR 0.32, P=0.004), including three patients in Arm A surviving >1 year.

Conclusions: Clinical studies of (90)Y-clivatuzumab tetraxetan combined with low-dose gemcitabine appear feasible in metastatic pancreatic cancer patients beyond 2nd line and a Phase III trial of this combination is now underway in this setting.
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http://dx.doi.org/10.1016/j.ejca.2015.06.119DOI Listing
September 2015

A computed tomography radiogenomic biomarker predicts microvascular invasion and clinical outcomes in hepatocellular carcinoma.

Hepatology 2015 Sep 1;62(3):792-800. Epub 2015 Jul 1.

Department of Radiology, University of California Los Angeles, David Geffen School of Medicine, Los Angeles, CA.

Unlabelled: Microvascular invasion (MVI) in hepatocellular carcinoma (HCC) is an independent predictor of poor outcomes subsequent to surgical resection or liver transplantation (LT); however, MVI currently cannot be adequately determined preoperatively. Radiogenomic venous invasion (RVI) is a contrast-enhanced computed tomography (CECT) biomarker of MVI derived from a 91-gene HCC "venous invasion" gene expression signature. Preoperative CECTs of 157 HCC patients who underwent surgical resection (N = 72) or LT (N = 85) between 2000 and 2009 at three institutions were evaluated for the presence or absence of RVI. RVI was assessed for its ability to predict MVI and outcomes. Interobserver agreement for scoring RVI was substantial among five radiologists (κ = 0.705; P < 0.001). The diagnostic accuracy, sensitivity, and specificity of RVI in predicting MVI was 89%, 76%, and 94%, respectively. Positive RVI score was associated with lower overall survival (OS) than negative RVI score in the overall cohort (P < 0.001; 48 vs. >147 months), American Joint Committee on Cancer tumor-node-metastasis stage II (P < 0.001; 34 vs. >147 months), and in LT patients within Milan criteria (P < 0.001; 69 vs. >147 months). Positive RVI score also portended lower recurrence-free survival at 3 years versus negative RVI score (P = 0.001; 27% vs. 62%).

Conclusion: RVI is a noninvasive radiogenomic biomarker that accurately predicts histological MVI in HCC surgical candidates. Its presence on preoperative CECT is associated with early disease recurrence and poor OS and may be useful for identifying patients less likely to derive a durable benefit from surgical treatment.
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http://dx.doi.org/10.1002/hep.27877DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4654334PMC
September 2015

Noninvasive image texture analysis differentiates K-ras mutation from pan-wildtype NSCLC and is prognostic.

PLoS One 2014 2;9(7):e100244. Epub 2014 Jul 2.

Imaging Endpoints Core Lab, Scottsdale, Arizona, United States of America; Virginia G. Piper Cancer Center Clinical Trials at Scottsdale Healthcare, Scottsdale, Arizona, United States of America.

Background: Non-invasive characterization of a tumor's molecular features could enhance treatment management. Quantitative computed tomography (CT) based texture analysis (QTA) has been used to derive tumor heterogeneity information, and the appearance of the tumors has been shown to relate to patient outcome in non-small cell lung cancer (NSCLC) and other cancers. In this study, we examined the potential of tumoral QTA to differentiate K-ras mutant from pan-wildtype tumors and its prognostic potential using baseline pre-treatment non-contrast CT imaging in NSCLC.

Methods: Tumor DNA from patients with early-stage NSCLC was analyzed on the LungCarta Panel. Cases with a K-ras mutation or pan-wildtype for 26 oncogenes and tumor suppressor genes were selected for QTA. QTA was applied to regions of interest in the primary tumor. Non-parametric Mann Whitney test assessed the ability of the QTA, clinical and patient characteristics to differentiate between K-ras mutation from pan-wildtype. A recursive decision tree was developed to determine whether the differentiation of K-ras mutant from pan-wildtype tumors could be improved by sequential application of QTA parameters. Kaplan-Meier survival analysis assessed the ability of these markers to predict survival.

Results: QTA was applied to 48 cases identified, 27 had a K-ras mutation and 21 cases were pan-wildtype. Positive skewness and lower kurtosis were significantly associated with the presence of a K-ras mutation. A five node decision tree had sensitivity, specificity, and accuracy values (95% CI) of 96.3% (78.1-100), 81.0% (50.5-97.4), and 89.6% (72.9-97.0); respectively. Kurtosis was a significant predictor of OS and DFS, with a lower kurtosis value linked with poorer survival.

Conclusions: Lower kurtosis and positive skewness are significantly associated with K-ras mutations. A QTA feature such as kurtosis is prognostic for OS and DFS. Non-invasive QTA can differentiate the presence of K-ras mutation from pan-wildtype NSCLC and is associated with patient survival.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0100244PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4079229PMC
February 2015

ALK molecular phenotype in non-small cell lung cancer: CT radiogenomic characterization.

Radiology 2014 Aug 2;272(2):568-76. Epub 2014 Jun 2.

From the Department of Radiological Sciences, David Geffen School of Medicine at UCLA, 10833 Le Conte Ave, Box 951721, CHS 17-135, Los Angeles, CA 90095-1721 (S.Y., C.M., M.D.K.); Scottsdale Medical Imaging, Scottsdale, Ariz (R.L.K.); Scottsdale Healthcare, Scottsdale, Ariz (R.L.K.); Departments of Vascular Interventional Radiology (R.O.) and Pathology (A.J.I.), Massachusetts General Hospital, Harvard Medical School, Boston, Mass; Department of Radiology, Mayo Clinic, Phoenix, Ariz (M.B.G.); Department of Radiology, Mayo Clinic, Scottsdale, Ariz (M.B.G.); Cancer Treatment Centers of America, Goodyear, Ariz (G.J.W.); Translational Genomics Research Institute, Phoenix, Ariz (G.J.W.); and Department of Internal Medicine, Seoul National University Hospital, Seoul, Republic of Korea (D.W.K.).

Purpose: To present a radiogenomic computed tomographic (CT) characterization of anaplastic lymphoma kinase (ALK)-rearranged non-small cell lung cancer (NSCLC) (ALK+).

Materials And Methods: In this HIPAA-compliant institutional review board-approved retrospective study, CT studies, ALK status, and clinical-pathologic data in 172 patients with NSCLC from three institutions were analyzed. A screen of 24 CT image traits was performed in a training set of 59 patients, followed by random forest variable selection incorporating 24 CT traits plus six clinical-pathologic covariates to identify a radiogenomic predictor of ALK+ status. This predictor was then validated in an independent cohort (n = 113). Test-for-accuracy and subset analyses were performed. A similar analysis was performed to identify a biomarker associated with shorter progression-free survival (PFS) after therapy with the ALK inhibitor crizotinib.

Results: ALK+ status was associated with central tumor location, absence of pleural tail, and large pleural effusion. An ALK+ radiogenomic CT status biomarker consisting of these three imaging traits with patient age of younger than 60 years showed strong discriminatory power for ALK+ status, with a sensitivity of 83.3% (15 of 18), a specificity of 77.9% (74 of 95), and an accuracy of 78.8% (89 of 113) in independent testing. The discriminatory power was particularly strong in patients with operable disease (stage IIIA or lower), with a sensitivity of 100.0% (five of five), a specificity of 88.1% (37 of 42), and an accuracy of 89.4% (42 of 47). Tumors with a disorganized vessel pattern had a shorter PFS with crizotinib therapy than tumors without this trait (11.4 vs 20.2 months, P = .041).

Conclusion: ALK+ NSCLC has distinct characteristics at CT imaging that, when combined with clinical covariates, discriminate ALK+ from non-ALK tumors and can potentially identify patients with a shorter durable response to crizotinib.
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http://dx.doi.org/10.1148/radiol.14140789DOI Listing
August 2014

Overview: progression-free survival as an endpoint in clinical trials with solid tumors.

Clin Cancer Res 2013 May;19(10):2607-12

Imaging Endpoints Core Lab, Scottsdale, Arizona, USA.

Progression-free survival (PFS) is increasingly used as an important and even a primary endpoint in randomized cancer clinical trials in the evaluation of patients with solid tumors for both practical and clinical considerations. Although in its simplest form, PFS is the time from randomization to a predefined endpoint, there are many factors that can influence the exact moment of when disease progression is recorded. In this overview, we review the circumstances that can devalue the use of PFS as a primary endpoint and attempt to provide a pathway for a future desired state when PFS will become not just a secondary alternative to overall survival but rather an endpoint of choice.
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http://dx.doi.org/10.1158/1078-0432.CCR-12-2934DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3654394PMC
May 2013

18-FDG PET/CT assessment of basal cell carcinoma with vismodegib.

Cancer Med 2012 Oct 17;1(2):230-6. Epub 2012 Sep 17.

Scottsdale Medical Imaging, Ltd. Scottsdale, AZ; Midwestern University Glendale, AZ, USA.

The use of 18-fluorodeoxyglucose (FDG) positron emission tomography with computed tomography (PET/CT) in subjects with advanced basal cell carcinoma (BCC) has not been fully explored due to the rarity of disease presentation. This study evaluated PET/CTs from subjects with advanced BCC participating in a phase I dose-escalation clinical trial of vismodegib. Fourteen subjects with BCC were imaged with 18-FDG PET/CT for lesion identification and response categorizing (European Organisation for Research and Treatment for Cancer [EORTC] and PET response criteria in solid tumors [PERCIST] 1.0). Several parameters including metabolic activity of target lesions, site of disease presentation and spread, treatment response, and prognostic significance of metabolic activity following therapy were evaluated. All subjects exhibited at least one hypermetabolic lesion. Most subjects had only four organ systems involved at study enrollment: skin-muscle (93%), lung (57%), lymph nodes (29%), and bone (21%). SUVmax measured across all lesions decreased (median 33%, SD ± 45%) following therapy with metabolic activity normalizing or disappearing in 42% of lesions. No significant difference was observed between EORTC and PERCIST 1.0. Subjects that demonstrated at least a 33% reduction in SUVmax from baseline had a significantly longer progression-free survival (PFS) (median 17 months, 95% confidence interval [CI] ±4 months vs. 9 months, 95% CI ±5 months, P = 0.038) and overall survival (OS) (median 24 months, 95% CI ±4 months vs. 17 months, 95% CI ±13 months, P = 0.019). BCC lesions are hypermetabolic on 18-FDG PET/CT. A decrease in SUVmax was associated with improved PFS and OS. These results further support the incorporation of 18-FDG PET/CT scans in advanced BCC management.
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http://dx.doi.org/10.1002/cam4.33DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3544445PMC
October 2012

Interpretation of PET scans: do not take SUVs at face value.

J Thorac Oncol 2012 Dec;7(12):1744-1746

Virginia G. Piper Cancer Center Clinical Trials at Scottsdale Healthcare, Scottsdale, Arizona; Imaging Endpoints Core Lab, Scottsdale, Arizona.

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http://dx.doi.org/10.1097/JTO.0b013e31827450aeDOI Listing
December 2012

Clonal evolution of a case of treatment refractory maxillary sinus carcinoma.

PLoS One 2012 28;7(9):e45614. Epub 2012 Sep 28.

The Translational Genomics Research Institute, Phoenix, AZ, USA.

Background: Maxillary sinus carcinoma (MSC) is a rare cancer of the head and neck region. Patients are treated with surgery, radiation therapy, and chemotherapy and the treatment regimen is based on patient's age, general health condition, disease stage, and its extent of spread. There is very little information available on the genetics of this disease. DNA content based flow sorting of tumor cells followed by array comparative genomic hybridization allows for high definition global assessment of distinct clonal changes within tumor populations.

Methods: We applied this technique to primary and metastatic samples collected from a patient with radio- and chemotherapy refractory maxillary sinus carcinoma to gauge the progression of this disease.

Results: A clonal KIT amplicon was present in aneuploid populations sorted from the primary tumor and in divergent subclones arising in metastatic foci found in the brain, lung, and jejunum. The evolution of these subclones was associated with distinct genetic aberrations and DNA ploidies.

Conclusion: The information presented here paves the path to understanding the development and progression of this disease.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0045614PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3460998PMC
March 2013

Radiogenomic analysis of breast cancer using MRI: a preliminary study to define the landscape.

AJR Am J Roentgenol 2012 Sep;199(3):654-63

Department of Radiological Sciences and Radiology-Pathology Program, University of California-Los Angeles, David Geffen School of Medicine, Los Angeles, CA 90095-1721, USA.

Objective: Molecular profiling studies have defined the increasing importance of gene expression phenotyping in breast cancer. However, the relationship between global transcriptomic profiles and the information provided by breast MRI remains to be examined. In this pilot study, our aim was to provide a preliminary radiogenomic association map linking MR image phenotypes to underlying global gene expression patterns in breast cancer.

Materials And Methods: From a multiinstitutional study, a total of 353 patients with a diagnosis of breast cancer were examined for gene expression analysis. Radiogenomic analysis was then performed on a subset of these patients (n = 10) who also underwent breast MRI. Two radiologists evaluated each MRI study across 26 predefined imaging phenotypes. Analyses were performed to correlate the expression and imaging data and to define associations between specific MR image phenotypes and gene sets of interest.

Results: High-level analysis revealed 21 imaging traits that were globally correlated (p < 0.05), with 71% of the total genes measured in patients with breast cancer. A significant correlation was identified between heterogeneous enhancement patterns and a previously described interferon breast cancer subtype (p < 0.01). We also identified 12 imaging traits that significantly correlated (false discovery rate < 0.25) with gene sets related to breast cancer and 11 traits correlated (false discovery rate < 0.25) to prognostic gene sets (van't Veer, wound response, and hypoxia metagene signatures) using gene enrichment analysis.

Conclusion: Radiogenomic analysis of breast cancer with MRI is a novel approach to understanding the underlying molecular biology of breast cancers.
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http://dx.doi.org/10.2214/AJR.11.7824DOI Listing
September 2012

Metastatic basal cell carcinoma in the era of hedgehog signaling pathway inhibitors.

Cancer 2012 Nov 17;118(21):5310-9. Epub 2012 Apr 17.

Virginia G. Piper Cancer Center Clinical Trials at Scottsdale Healthcare, Scottsdale, Arizona; Translational Genomics Research Institute, Phoenix, AZ 85258, USA.

Background: Inhibition of the hedgehog signaling pathway (HHSP) for the treatment of locally advanced basal cell carcinoma (BCC) and metastatic BCC (mBCC) has produced promising results. Typically, mBCC is not taken into consideration during the workup of a patient with multifocal metastatic disease who has a history of BCC. The objective of the current review, in which the authors evaluated the time from the first BCC diagnosis to metastasis, location of disease, and radiographic features, was to contribute to the general knowledge and awareness among providers, patients, and support groups about mBCC and to provide an outlook for the future of treatments for mBCC. A literature review on mBCC and a review of records from patients with mBCC who presented to Virginia G. Piper Cancer Center Clinical Trials (an oncology clinical trials center) were conducted. The clinical and radiographic findings of 22 patients with mBCC who were evaluated at that center from the initiation of smoothened (SMO) antagonist trials were analyzed along with a review of BCC epidemiology and pathogenesis, the HHSP, and current and future treatments for this rare presentation of the most common malignancy. The results indicated that, in the last 5 years, there has been a plethora of new agents targeting SMO, a key component of the HHSP that, for the majority of patients with mBCC, may be a good match for targeting tumor genetic vulnerability. Like with other targeted therapy for uncommon malignancies, such as chronic myelogenous leukemia and gastrointestinal stromal tumors, the authors anticipate that there will be clinical development of next-generation HHSP inhibitors to combat mBCCs that are nonresponsive to or progress on current SMO antagonists.
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http://dx.doi.org/10.1002/cncr.27532DOI Listing
November 2012

Gemcitabine plus nab-paclitaxel is an active regimen in patients with advanced pancreatic cancer: a phase I/II trial.

J Clin Oncol 2011 Dec 3;29(34):4548-54. Epub 2011 Oct 3.

TGen/Virginia G Piper Cancer Ctr, 445 N Fifth St, Suite 600, Phoenix, AZ 85004, USA.

Purpose: The trial objectives were to identify the maximum-tolerated dose (MTD) of first-line gemcitabine plus nab-paclitaxel in metastatic pancreatic adenocarcinoma and to provide efficacy and safety data. Additional objectives were to evaluate positron emission tomography (PET) scan response, secreted protein acidic and rich in cysteine (SPARC), and CA19-9 levels in relation to efficacy. Subsequent preclinical studies investigated the changes involving the pancreatic stroma and drug uptake.

Patients And Methods: Patients with previously untreated advanced pancreatic cancer were treated with 100, 125, or 150 mg/m(2) nab-paclitaxel followed by gemcitabine 1,000 mg/m(2) on days 1, 8, and 15 every 28 days. In the preclinical study, mice were implanted with human pancreatic cancers and treated with study agents.

Results: A total of 20, 44, and three patients received nab-paclitaxel at 100, 125, and 150 mg/m(2), respectively. The MTD was 1,000 mg/m(2) of gemcitabine plus 125 mg/m(2) of nab-paclitaxel once a week for 3 weeks, every 28 days. Dose-limiting toxicities were sepsis and neutropenia. At the MTD, the response rate was 48%, with 12.2 median months of overall survival (OS) and 48% 1-year survival. Improved OS was observed in patients who had a complete metabolic response on [(18)F]fluorodeoxyglucose PET. Decreases in CA19-9 levels were correlated with increased response rate, progression-free survival, and OS. SPARC in the stroma, but not in the tumor, was correlated with improved survival. In mice with human pancreatic cancer xenografts, nab-paclitaxel alone and in combination with gemcitabine depleted the desmoplastic stroma. The intratumoral concentration of gemcitabine was increased by 2.8-fold in mice receiving nab-paclitaxel plus gemcitabine versus those receiving gemcitabine alone.

Conclusion: The regimen of nab-paclitaxel plus gemcitabine has tolerable adverse effects with substantial antitumor activity, warranting phase III evaluation.
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http://dx.doi.org/10.1200/JCO.2011.36.5742DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3565012PMC
December 2011

Biomarkers associated with metastasis of lung cancer to brain predict patient survival.

Int J Data Min Bioinform 2011 ;5(3):287-307

Computational Biology Division, Translational Genomics Research Institute, Phoenix, AZ 85004, USA.

MicroRNAs influence cell physiology; alteration in miRNA regulation can be implicated in carcinogenesis and disease progression. Generally, one miRNA is predicted to regulate several hundred genes, and as a result, miRNAs could serve as a better classifier than gene expression. We combine validated miRNA expression values with imaging features to classify NSCLC brain mets from non-brain mets and identify possible biomarkers of brain mets. This research involves comprehensive miRNA expression profiling, evaluation of normalisation techniques and combination of miRNA with imaging features FDG-PET/CT and CT Scan. The biomarkers were validated on an independent data set to predict potential brain mets.
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http://dx.doi.org/10.1504/ijdmb.2011.040385DOI Listing
September 2011

Automated registration of sequential breath-hold dynamic contrast-enhanced MR images: a comparison of three techniques.

Magn Reson Imaging 2011 Jun 29;29(5):668-82. Epub 2011 Apr 29.

Department of Electrical and Computer Engineering, The University of Arizona, Tucson, AZ 85721-0104, USA.

Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) is increasingly in use as an investigational biomarker of response in cancer clinical studies. Proper registration of images acquired at different time points is essential for deriving diagnostic information from quantitative pharmacokinetic analysis of these data. Motion artifacts in the presence of time-varying intensity due to contrast enhancement make this registration problem challenging. DCE-MRI of chest and abdominal lesions is typically performed during sequential breath-holds, which introduces misregistration due to inconsistent diaphragm positions and also places constraints on temporal resolution vis-à-vis free-breathing. In this work, we have employed a computer-generated DCE-MRI phantom to compare the performance of two published methods, Progressive Principal Component Registration and Pharmacokinetic Model-Driven Registration, with Sequential Elastic Registration (SER) to register adjacent time-sample images using a published general-purpose elastic registration algorithm. In all three methods, a 3D rigid-body registration scheme with a mutual information similarity measure was used as a preprocessing step. The DCE-MRI phantom images were mathematically deformed to simulate misregistration, which was corrected using the three schemes. All three schemes were comparably successful in registering large regions of interest (ROIs) such as muscle, liver, and spleen. SER was superior in retaining tumor volume and shape, and in registering smaller but important ROIs such as tumor core and tumor rim. The performance of SER on clinical DCE-MRI data sets is also presented.
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http://dx.doi.org/10.1016/j.mri.2011.02.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3100446PMC
June 2011

MicroRNA-328 is associated with (non-small) cell lung cancer (NSCLC) brain metastasis and mediates NSCLC migration.

Int J Cancer 2011 Dec 29;129(11):2621-31. Epub 2011 Mar 29.

Cancer and Cell Biology Division, Translational Genomics Research Institute, Phoenix, AZ, USA.

Brain metastasis (BM) can affect ∼ 25% of nonsmall cell lung cancer (NSCLC) patients during their lifetime. Efforts to characterize patients that will develop BM have been disappointing. microRNAs (miRNAs) regulate the expression of target mRNAs. miRNAs play a role in regulating a variety of targets and, consequently, multiple pathways, which make them a powerful tool for early detection of disease, risk assessment, and prognosis. We investigated miRNAs that may serve as biomarkers to differentiate between NSCLC patients with and without BM. miRNA microarray profiling was performed on samples from clinically matched NSCLC from seven patients with BM (BM+) and six without BM (BM-). Using t-test and further qRT-PCR validation, eight miRNAs were confirmed to be significantly differentially expressed. Of these, expression of miR-328 and miR-330-3p were able to correctly classify BM+ vs. BM- patients. This classifier was used on a validation cohort (n = 15), and it correctly classified 12/15 patients. Gene expression analysis comparing A549 parental and A549 cells stably transfected to over-express miR-328 (A549-328) identified several significantly differentially expressed genes. PRKCA was one of the genes over-expressed in A549-328 cells. Additionally, A549-328 cells had significantly increased cell migration compared to A549 cells, which was significantly reduced upon PRKCA knockdown. In summary, miR-328 has a role in conferring migratory potential to NSCLC cells working in part through PRKCA and with further corroboration in additional independent cohorts, these miRNAs may be incorporated into clinical treatment decision making to stratify NSCLC patients at higher risk for developing BM.
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http://dx.doi.org/10.1002/ijc.25939DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3154499PMC
December 2011

Unexpected focal hypermetabolic activity in the breast: significance in patients undergoing 18F-FDG PET/CT.

AJR Am J Roentgenol 2006 Jul;187(1):81-5

Department of Research, Scottsdale Medical Imaging, 3501 N Scottsdale Rd., Ste. 130, Scottsdale, AZ 85251, USA.

Objective: We describe the significance of detecting focal areas of hypermetabolism in the breast in patients undergoing PET/CT for reasons other than for breast cancer detection or staging.

Conclusion: When evaluated, almost all of the abnormal foci detected in the breast subsequently proved to be breast carcinoma, specifically infiltrating ductal carcinoma.
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http://dx.doi.org/10.2214/AJR.05.0548DOI Listing
July 2006