Decrease In Standardized Uptake Value Research Articles

A Phase I/IIa Prospective, Randomized, Open-Label Study on the Safety and Efficacy of Nebulized Liposomal Amphotericin for Invasive Pulmonary Aspergillosis.

Although nebulized liposomal amphotericin B (NLAB) is being used in invasive pulmonary aspergillosis (IPA) prophylaxis, no clinical trial has shown its efficacy as a therapeutic strategy. NAIFI is the inaugural randomized, controlled clinical trial designed to examine the safety and effectiveness of NLAB (dosage: 25 mg in 6 mL, three times per week for 6 weeks) against a placebo, in the auxiliary treatment of IPA. Throughout the three-year clinical trial, thirteen patients (six NLAB, seven placebo) were included, with 61% being onco-hematological with less than 100 neutrophils/μL. There were no significant differences noted in their pre- and post-nebulization results of forced vital capacity (FVC), forced expiratory volume in 1 s (FEV1), and oxygen saturation between the groups. Neither bronchospasm nor serum amphotericin B levels were reported in any patients given NLAB. 18F-Fluorodeoxyglucose positron emission tomography (FDG-PET-TC) was carried out at the baseline and after 6 weeks. A notable decrease in median SUV (standardized uptake value) was observed in NLAB patients after 6 weeks (-3.6 vs. -0.95, p: 0.039, one tail). Furthermore, a reduction in serum substance galactomannan and beta-D-Glucan was identified within NLAB recipients. NLAB is well tolerated and safe for patients with IPA. Encouraging indirect efficacy data have been derived from image monitoring or biomarkers. However, further studies involving more patients are necessary.

NEIM-14 PET/MRI DETECTS A RAPID DECREASE IN CEREBRAL BLOOD FLOW IN GLIOBLASTOMA FOLLOWING BEVACIZUMAB INFUSION

Abstract BACKGROUND The impacts of bevacizumab on the vasculature and metabolism of glioblastoma have been understudied. Previous work has shown that perfusion measurements of lesions decrease weeks after infusion. Metabolic consequences, either direct or as sequelae of vascular changes, have also been proposed. The timing of both processes in humans, however, is unclear. We aimed to study changes to the vasculature and metabolism of glioblastoma after the administration of bevacizumab. METHODS Patients (n = 8) diagnosed with recurrent glioblastoma requiring bevacizumab were enrolled. Baseline scans were acquired with a GE Healthcare SIGNA PET/MRI scanner. Following the first infusion of bevacizumab (7.5 mg/kg), repeat scans were obtained within two days and two weeks. All scans were co-registered and analyzed using 3D Slicer. Cerebral blood flow (CBF) and standard uptake value (SUV) measures were normalized by taking the ratio of the mean tumor and contralateral region values, and the ratios at different time points were compared using Wilcoxon signed-rank tests. RESULTS A statistically significant decrease in tumor CBF was detected within two days of infusion (0.88 ± 0.36 vs. 0.79 ± 0.29, p = 0.01), but no significant decrease in SUV was detected within the same timeframe (0.89 ± 0.36 vs. 0.88 ± 0.39, p = 0.26). No statistically significant drop was detected at two weeks in our sample. CONCLUSIONS Our results provide evidence that bevacizumab decreases glioblastoma blood flow within two days of the infusion. The measure of tumor metabolism also trended downward, though not significantly. Taken together, these data support a model by which bevacizumab rapidly affects VEGF-mediated vascular changes within the tumor, withpotential effects on tumor metabolism over a longer timeframe. These findings enrich our understanding of the impacts on glioblastoma of bevacizumab, which has a continued high clinical utility that is underscored by its ubiquity in the neuro-oncology clinic.

Prostate-Specific Membrane Antigen PET Response Associates with Metastasis-Free Survival Following Stereotactic Ablative Radiation Therapy in Oligometastatic Castration-Sensitive Prostate Cancer

<h3>Purpose/Objective(s)</h3> Emerging data suggest metastasis-directed therapy (MDT) improves outcomes in patients with oligometastatic castration-sensitive prostate cancer (omCSPC). Prostate-specific membrane antigen positron emission tomography (PSMA-PET/CT) can detect occult metastatic disease and has been proposed as a biomarker for treatment response. Herein we identify and validate a PSMA-PET biomarker for clinical outcomes following MDT in omCSPC. <h3>Materials/Methods</h3> This was an international multi-institutional retrospective study of two independent cohorts of omCSPC, defined as ≤3 lesions, treated with metastasis-directed stereotactic ablative radiation therapy (SABR). Patients underwent PSMA-PET/CT prior to and 3-6 months after treatment. Pre- and post-SABR PSMA-PET/CT standardized uptake value (SUV) was measured for all lesions and PSMA response defined discretely using a cutpoint of ≥ 30% decrease in SUV_max. PSMA-PET response was correlated with lesion local control (LLC), and metastasis-free survival (MFS), defined per ICECaP working group by a new metastasis on conventional imaging alone (not including pelvic lymph node metastases) or death. <h3>Results</h3> A total of 131 patients (discovery n=35, validation n=96) with 261 treated metastases were included in the analysis, with median follow-up of 29 months (IQR 18.5-41.3). Following SABR, 78.4% of lesions experienced a partial or complete PSMA response. Multivariable analysis demonstrated SUV response significantly associated with improved LLC (HR=0.10, 95%CI 0.04-0.26; p<0.01). Patients with PSMA response in all lesions experienced significantly better MFS (HR=0.37, 95%CI 0.21-0.65; p<0.01) compared to their counterparts, and this maintained significance within both the discovery (p=0.02) and validation (p<0.01) cohorts. <h3>Conclusion</h3> Following SABR, PSMA-PET response is a robust and externally validated radiographic biomarker for MFS in omCSPC. This approach holds promise for guiding clinical management of omCSPC and should be validated as an early response indicator biomarker in localized and other advanced states of prostate cancer.

Non-Invasive Characterization of Experimental Bone Metastasis in Obesity Using Multiparametric MRI and PET/CT.

Simple SummaryThe bone marrow microenvironment, particularly adipocytes, plays a pivotal role as growth mediators of disseminated tumor cells in the bone marrow. In this prospective longitudinal study, we used multimodal and multiparametric imaging from magnetic resonance (MRI) and hybrid imaging (positron emission tomography and computed tomography; PET/CT) to non-invasively characterize the pathophysiologic processes of experimental bone metastases in obese and non-obese individuals. Obesity was induced by a high-fat diet (HFD) in rats and mice, resulting in enhanced glucose metabolism and angiogenic activity in metastatic bone lesions, as shown by significantly increased dynamic contrast-enhanced MRI and [18F]fluorodeoxyglucose PET/CT parameters in HFD-fed animals. These results were validated with immunohistochemistry and gene expression analysis. In conclusion, pathophysiological processes can be non-invasively assessed by MRI and PET/CT, opening novel avenues for quantitative assessment of follow-up and monitoring of treatment response in skeletal lesions.The growth of primary tumors and metastases is associated with excess body fat. In bone metastasis formation, the bone marrow microenvironment, and particularly adipocytes, play a pivotal role as growth mediators of disseminated tumor cells in the bone marrow. The aim of the present study is to non-invasively characterize the pathophysiologic processes in experimental bone metastasis resulting from accelerated tumor progression within adipocyte-rich bone marrow using multimodal imaging from magnetic resonance imaging (MRI) and positron emission tomography/computed tomography (PET/CT). To achieve this, we have employed small animal models after the administration of MDA-MB 231 breast cancer and B16F10 melanoma cells into the bone of nude rats or C57BL/6 mice, respectively. After tumor cell inoculation, ultra-high field MRI and µPET/CT were used to assess functional and metabolic parameters in the bone marrow of control animals (normal diet, ND), following a high-fat diet (HFD), and/or treated with the peroxisome proliferator-activated receptor-gamma (PPARγ) antagonist bisphenol-A-diglycidylether (BADGE), respectively. In the bone marrow of nude rats, dynamic contrast-enhanced MRI (DCE-MRI) and diffusion-weighted imaging (DWI), as well as [18F]fluorodeoxyglucose-PET/CT([18F]FDG-PET/CT), was performed 10, 20, and 30 days after tumor cell inoculation, followed by immunohistochemistry. DCE-MRI parameters associated with blood volume, such as area under the curve (AUC), were significantly increased in bone metastases in the HFD group 30 days after tumor cell inoculation as compared to controls (p < 0.05), while the DWI parameter apparent diffusion coefficient (ADC) was not significantly different between the groups. [18F]FDG-PET/CT showed an enhanced glucose metabolism due to increased standardized uptake value (SUV) at day 30 after tumor cell inoculation in animals that received HFD (p < 0.05). BADGE treatment resulted in the inversion of quantitative DCE-MRI and [18F]FDG-PET/CT data, namely a significant decrease in AUC and SUV in HFD-fed animals as compared to ND-fed controls (p < 0.05). Finally, immunohistochemistry and qPCR confirmed the HFD-induced stimulation in vascularization and glucose activity in murine bone metastases. In conclusion, multimodal and multiparametric MRI and [18F]FDG-PET/CT were able to derive quantitative parameters in bone metastases, revealing an increase in vascularization and glucose metabolism following HFD. Thus, non-invasive imaging may serve as a biomarker for assessing the pathophysiology of bone metastasis in obesity, opening novel options for therapy and treatment monitoring by MRI and [18F]FDG-PET/CT.

Abstract P3-02-03: Quantitative molecular breast imaging for early prediction of neoadjuvant systemic therapy response in locally advanced breast cancer patients

Abstract BACKGROUND: Increasing use of neoadjuvant systemic therapy (NAT) for early and locally advanced breast cancer led to critical need for development of tools capable of early treatment response assessment after NAT. Tc-99m sestamibi Molecular breast Imaging (MBI) as a functional imaging modality has a promise to detect changes in the tumor prior to anatomical changes detected by mammogram or ultrasound. PURPOSE: To evaluate the ability of quantitative MBI parameters to predict pathologic complete response (pCR) after completion of NAT in breast cancer patients. MATERIALS AND METHODS: Patients with invasive breast cancer (T1-T4, N0-N3, M0) planned for NAT followed by surgery were enrolled in a prospective IRB approved trial. MBI was performed at baseline and after two cycles of NAT. Patient demographic and tumor biology information (Ki-67, HER2, ER/PR) was collected. MBI images were quantified using a novel approach with corrections for scatter and attenuation and regions of interest (ROI) were drawn over tumors to compute three quantitative MBI uptake metrics for correlation with pathologic response: MBI-specific standardized uptake value (SUV), tumor to background ratio (TBR), and tumor volume. Pathologic complete response was determined based on final histopathology report at the time of surgery as absence of the invasive disease in the breast and axillary lymph nodes. MBI metrics at baseline, after 2 cycles of NAT and interval change were correlated with pCR and tumor biology using the Wilcoxon Rank Sum test, Kruskal-Wallis test or Fisher’s exact test. Statistical analysis was carried out using R (version 3.6.3, R Development Core Team). RESULTS: A total of 70 patients with median age 47.5 years (range 30-77) were included in the analysis. Breast cancer subtypes were: HER2 negative (ER/PR+) 35.7% (25/70), HER2 positive (ER/PR +/-) 35.7% (25/70), and triple negative (HER2-, ER/PR-) 28.6% (20/70). Change in SUV after 2 cycles of NAT was higher in patients with pCR compared to those who did not achieve pCR (mean decrease in SUV of 15.57 and 4.83 respectively, p&amp;lt;0.001). Additionally, change in TBR in patients with pCR was also higher compared to patients who did not achieve pCR (mean decreases of 1.14 and 0.56, respectively, p&amp;lt;0.001). No correlation was found between baseline SUV, baseline TBR, change in volume, and pCR. CONCLUSION: MBI-specific SUV and TBR changes after two cycles of NAT correlate and may predict pCR in patients with locally advanced breast cancer. Quantitative MBI parameters are novel promising imaging tools that may help to detect early clinical benefit and optimize management in patients receiving NAT. Citation Format: Miral M Patel, Beatriz E Adrada, Benjamin Lopez, Rosalind P Candelaria, Jia Sun, Medine Boge, Rania M Mohamed, Nabil Elshafeey, Gary Whitman, MD, Huong T Le-Petross, Lumarie Santiago, Marion E Scoggins, Deanna Lane, Tanya Moseley, Galit Zylberman, Jerica Saddler, Jessica WT Leung, Wei T Yang, Vincente Valero, S Cheenu Kappadath, Gaiane M Rauch. Quantitative molecular breast imaging for early prediction of neoadjuvant systemic therapy response in locally advanced breast cancer patients [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P3-02-03.

NEIM-05. [GA68]DOTATATE PET/MRI-BASED RADIOSURGICAL RESPONSE ASESSMENT IN MENINGIOMA

Abstract PURPOSE Postoperative PET/MRI with [68Ga]-DOTATATE can differentiate residual meningioma from postsurgical change, aid in target delineation, and portend a more favorable dosimetry with decreased PTV and organ-at-risk dose. Our purpose was to demonstrate utility of DOTATATE PET/MR for radiosurgical treatment (RT) response assessment in meningiomas. METHODS Patients underwent postoperative radiation treatment planning using DOTATATE PET/MRI as part of our IRB-approved prospective trial. Both DOTATATE PET and gadolinium-enhanced T1 weighted MR imaging were incorporated in RT-planning. All patients underwent follow-up DOTATATE PET/MRI at 6-12 months following completion of radiosurgery. Maximum absolute standardized uptake value (SUV) and SUV ratio (SUVR) of lesion/ superior sagittal sinus SUV were obtained. RANO criteria were applied to determine significance of change in size. Statistical analyses were performed using paired t-tests. RESULTS 13 patients (15% WHO-I, 54% WHO-II, 23% WHO-III, 8% WHO grade unknown) were followed postoperatively with pre- and post-RT DOTATATE PET/MRI. 29 meningiomas were treated. 46% (6/13) of subjects received SBRT and 54% (7/13) received SRS. Post-RT DOTATATE PET/MRI demonstrated a 46.4% SUV decrease (p-value = 0.0001) and a 60.8% SUVR decrease (p-value &amp;lt; 0.0001). Of 21 measurable lesions, the size product decreased by 21%; while this decrease was statistically significant (p-value = 0.0008), it was below the 25% decrease defined as clinically significant by RANO guidelines. To date, all patients remain stable radiographically without evidence of recurrence (mean follow-up post RT: 14 months; range: 6-24 months). CONCLUSIONS DOTATATE PET SUV and SUVR demonstrated marked, significant decrease post radiosurgery. Lesion size decrease was statistically significant but not clinically significant by RANO criteria. DOTATATE PET/MR thus represents a promising approach to aid in response assessment for radiosurgically treated meningiomas. Longer-term follow-up is needed to determine the correlation between the degree of post-RT SUV and/or SUVR decrease and progression-free-survival.

Evaluation of response using FDG-PET/CT and diffusion weighted MRI after radiochemotherapy of pancreatic cancer: a\xa0non-randomized, monocentric phase\xa0II clinical trial\u2014PaCa-DD-041 (Eudra-CT 2009-011968-11)

BackgroundPancreatic cancer is a devastating disease with a 5-year survival rate of 20–25%. As approximately only 20% of patients diagnosed with pancreatic cancer are initially staged as resectable, it is necessary to evaluate new therapeutic approaches. Hence, neoadjuvant (radio)chemotherapy is a promising therapeutic option, especially in patients with a borderline resectable tumor. The aim of this non-randomized, monocentric, prospective, phase II clinical study was to assess the prognostic value of functional imaging techniques, i.e., [18F]2-fluoro-2-deoxy-d-glucose positron emission tomography/computed tomography (FDG-PET/CT) and diffusion weighted magnetic resonance imaging (DW-MRI), prior to and during neoadjuvant radiochemotherapy.MethodsPatients with histologically proven resectable, borderline resectable or unresectable non-metastatic pancreatic adenocarcinoma received induction chemotherapy followed by neoadjuvant radiochemotherapy. Patients underwent FDG-PET/CT and DW-MRI including T1- and T2-weighted sequences prior to and after neoadjuvant chemotherapy as well as following induction radiochemotherapy. The primary endpoint was the evaluation of the response as quantified by the standardized uptake value (SUV) measured with FDG-PET. Response to treatment was evaluated by FDG-PET and DW-MRI during and after the neoadjuvant course. Morphologic staging was performed using contrast-enhanced CT and contrast-enhanced MRI to decide inclusion of patients and resectability after neoadjuvant therapy. In those patients undergoing subsequent surgery, imaging findings were correlated with those of the pathologic resection specimen.ResultsA total of 25 patients were enrolled in the study. The response rate measured by FDG-PET was 85% with a statistically significant decrease of the maximal SUV (SUVmax) during therapy (p < 0.001). Using the mean apparent diffusion coefficient (ADC), response was not detectable with DW-MRI. After neoadjuvant treatment 16 patients underwent surgery. In 12 (48%) patients tumor resection could be performed. The median overall survival of all patients was 25 months (range: 7–38 months).ConclusionBased on these limited patient numbers, it was possible to show that this trial design is feasible and that the neoadjuvant therapy regime was well tolerated. FDG-PET/CT may be a reliable method to evaluate response to the combined therapy. In contrast, when evaluating the response using mean ADC, DW-MRI did not show conclusive results.

Physiological Appearance of Hybrid FDG–Positron Emission Tomography/Computed Tomography Imaging Following Uncomplicated Endovascular Aneurysm Sealing Using the Nellix Endoprosthesis

Purpose: To investigate the physiological uptake of hybrid fluorine-18-fluorodeoxyglucose (FDG)–positron emission tomography/computed tomography (PET/CT) before and after an uncomplicated endovascular aneurysm sealing (EVAS) procedure as a possible tool to diagnose EVAS graft infection and differentiate from postimplantation syndrome. Materials and Methods: Eight consecutive male patients (median age 78 years) scheduled for elective EVAS were included in the prospective study (ClinicalTrials.gov identifier NCT02349100). FDG-PET/CT scans were performed in all patients before the procedure and 6 weeks after EVAS. The abdominal aorta was analyzed in 4 regions: suprarenal, infrarenal neck, aneurysm sac, and iliac. The following parameters were obtained for each region: standard uptake value (SUV), tissue to background ratio (TBR), and visual examination of FDG uptake to ascertain its distribution. Demographic data were obtained from medical files and scored based on reporting standards. Results: Visual examination showed no difference between pre- and postprocedure FDG uptake, which was homogenous. In the suprarenal region no significant pre- and postprocedure differences were observed for the SUV and TBR parameters. The infrarenal neck region showed a significant decrease in the SUV and no significant decrease in the TBR. The aneurysm sac and iliac regions both showed a significant decrease in SUV and TBR between the pre- and postprocedure scans. Conclusion: Physiological FDG uptake after EVAS was stable or decreased with regard to the preprocedure measurements. Future research is needed to assess the applicability and cutoff values of FDG-PET/CT scanning to detect endograft infection after EVAS.

An Efficient Automated Radiosynthesis and Bioactivity Confirmation of VMAT2 Tracer [18F]FP-(+)-DTBZ.

The aim of this study was to optimize the radiolabeling method of [18F]fluoropropyl-(+)-dihydrotetrabenazine ([18F]FP-(+)-DTBZ) to fulfill the demand of preclinical and clinical application. Optimized labeling conditions were performed by altering the molar ratio of precursor to base (P/B), base species, solvents, reaction temperature, reaction time, and precursor concentration through manual radiosynthesis of [18F]FP-(+)-DTBZ. The conditions with the highest radiochemical yield (RCY) were applied to automated radiosynthesis, and the crude product was purified with a Sep-Pak Plus C18 cartridge. Quality control and stability of [18F]FP-(+)-DTBZ were carried out by HPLC. In vitro cellular uptake and blocking assays were conducted in human neuroblastoma cell line SH-SY5Y. In vivo imaging with small animal positron emission tomography (microPET) was performed with Sprague-Dawley rats. Under the optimized conditions (P/K2CO3 = 1:8, heating at 120°C for 3min in dimethyl sulfoxide), an RCY of 88.7% was obtained with 1.0mg precursor. The optimized reaction conditions were successfully applied to an automated module and gave a high activity yield (AY) of 30-55% in about 40min with a > 99.0% radiochemical purity (RCP) and a > 44.4GBq/μmol molar activity (Am). Stability test displayed that the RCP retained > 98.0% in 8h in saline and in phosphate buffer saline (PBS, pH7.4). In vitro cellular uptake assay showed accumulation of [18F]FP-(+)-DTBZ in SH-SY5Y cells, which could be significantly inhibited by vesicular monoamine transporter 2 (VMAT2) inhibitor DTBZ. MicroPET images of rat brain displayed that the striatum showed the highest uptake with a standardized uptake value (SUV) of 3.91 ± 0.30 at ~ 70min. Co-injection with DTBZ (1.0mg/kg) resulted in a 75% decrease of the striatal SUV, confirming the specificity of [18F]FP-(+)-DTBZ to VMAT2. We obtained an optimized radiolabeling method of [18F]FP-(+)-DTBZ and successfully applied it to a commercial available module. The automated synthesis gave a high AY and RCP of [18F]FP-(+)-DTBZ with high and specific binding to VMAT2, facilitating its routine application for VMAT2 tracing.

Efficacy and safety of neoadjuvant PD-1 blockade with sintilimab in resectable squamous non-small cell lung cancer (sqNSCLC).

8531 Background: NSCLC patients who have potentially resectable disease often subsequently relapse after surgery. New therapy that prevents relapse after surgery is desperately needed. In this study, we tested the efficacy and safety of neoadjuvant sintilimab, an anti-PD-1 antibody, for patients with resectable sqNSCLC in China. Methods: All patients had treatment-naïve resectable sqNSCLC (stage IB-IIIA) that was confirmed by histopathology. Patients received two cycles of sintilimab (200 mg IV) on Day 1 and 22. Surgery was performed between Day 29-43. An enhanced PET/CT was obtained at baseline and seven days prior to surgery. Preliminary analysis of safety profile and efficacy was planned after at least 20 patients had received operation. Results: As of Jan. 28, 2019, 22 patients (20 males and 2 females) with sqNSCLC received two doses of sintilimab followed by radical resection. The median age was 61.5 yr (range, 48 to 70). Six (27.3%) and four (18.2%) patients experienced neoadjuvant treatment emergent adverse events (TEAEs) and neoadjuvant treatment-related AEs (TRAEs), respectively. Most of the TEAEs and TRAEs were grade 1 or 2. Three patients achieved radiological partial response: an ORR of 13.6% based on RECIST 1.1. Ten patients (45.5%) achieved a major pathologic response (MPR, ≤10% viable tumor cells), including four (18.2%) had complete pathologic response (no viable tumor cell). There was a direct correlation between pathological response and decrease in the standardized uptake values (SUV) in the primary tumor. Among nine patients with &gt; 30% decrease of SUV, eight had MPR, compared with no MRP response in the 11 patients with ≤30% decrease of SUV. Conclusions: Neoadjuvant sintilimab for sqNSCLC patients was tolerable and the 45.5% MRP rate is encouraging. A decrease in SUV may be predictive of pathologic response after PD-1 therapy in sqNSCLC. Clinical trial information: ChiCTR-OIC-17013726.

[18F]Fluorocholine and [18F]Fluoroacetate PET as Imaging Biomarkers to Assess Phosphatidylcholine and Mitochondrial Metabolism in Preclinical Models of TSC and LAM.

Tuberous sclerosis complex (TSC) is an autosomal dominant disorder caused by inactivating mutations of the TSC1 or TSC2 gene, characterized by neurocognitive impairment and benign tumors of the brain, skin, heart, and kidneys. Lymphangioleiomyomatosis (LAM) is a diffuse proliferation of α-smooth muscle actin-positive cells associated with cystic destruction of the lung. LAM occurs almost exclusively in women, as a TSC manifestation or a sporadic disorder (TSC1/TSC2 somatic mutations). Biomarkers of whole-body tumor burden/activity and response to rapalogs or other therapies remain needed in TSC/LAM. These preclinical studies aimed to assess feasibility of [18F]fluorocholine (FCH) and [18F]fluoroacetate (FACE) as TSC/LAM metabolic imaging biomarkers. We previously reported that TSC2-deficient cells enhance phosphatidylcholine synthesis via the Kennedy pathway. Here, we show that TSC2-deficient cells exhibit rapid uptake of [18F]FCH in vivo and can be visualized by PET imaging in preclinical models of TSC/LAM, including subcutaneous tumors and pulmonary nodules. Treatment with rapamycin (72 hours) suppressed [18F]FCH standardized uptake value (SUV) by >50% in tumors. Interestingly, [18F]FCH-PET imaging of TSC2-deficient xenografts in ovariectomized mice also showed a significant decrease in tumor SUV. Finally, we found rapamycin-insensitive uptake of FACE by TSC2-deficient cells in vitro and in vivo, reflecting its mitochondrial accumulation via inhibition of aconitase, a TCA cycle enzyme. Preclinical models of TSC2 deficiency represent informative platforms to identify tracers of potential clinical interest. Our findings provide mechanistic evidence for testing the potential of [18F]FCH and [18F]FACE as metabolic imaging biomarkers for TSC and LAM proliferative lesions, and novel insights into the metabolic reprogramming of TSC tumors.

Change in standardized uptake values in delayed 18F-FDG positron emission tomography images in hepatocellular carcinoma.

Delayed 18F-2-fluoro-2-deoxy-d-glucose (18F-FDG) positron emission tomography (PET) imaging has been associated with improved diagnostic yield in several malignancies; however, data on the use of delayed imaging in patients with hepatocellular carcinoma (HCC) is scarce. This study aimed to examine tumoral and background standardized uptake value (SUV) alterations in dual-phase 18F-FDG PET/computed tomography (CT) imaging.Fifty-two HCC cases underwent dual-time-point 18F-FDG PET/CT examination where early and delayed images were obtained. The maximum and mean SUVs (SUVmax and SUVmean) of the tumor were determined for both time points. Similarly, the average SUVmean were also determined for background (liver, soft tissue, and spleen). Changes in tumoral and background SUV between early and delayed images were examined.The mean age was 62.0 ± 12.9 years (range, 20–88 years) and the majority of the patients were men (86.5%). Tumor SUVs, both tumor SUVmean and tumor SUVmax, significantly increased at delayed images when compared to early images. In contrast, the average SUVmean for the liver, soft tissue, and spleen significantly decreased at delayed images.A significant increase in tumor SUV in delayed images in contrast to a significant decrease in background SUVs suggests that delayed images in HCC may contribute to diagnostic performance through a potential increase in the contrast between the tumor and background. However, further studies with larger sample sizes including patients with benign lesions and different grades of the disease are warranted to better elucidate the diagnostic contribution as well as the association of delayed imaging values with prognosis.

Prognostic value of 18F-FDG PET/CT and C-MYC gene rearrangement on chemotherapy in patients with diffuse large B-cell lymphoma

Objective To evaluate the prognostic value of the maximum standardized uptake value decrease proportion (ΔSUVmax%) on 18F-fluorodeoxyglucose (FDG) PET/CT imaging and C-MYC gene in diffuse large B cell lymphoma (DLBCL), and to find the optimal time of PET/CT imaging. Methods From September 2010 to February 2016, 171 patients (87 males, 84 females, average age: (50.66±2.56) years) with pathologically confirmed DLBCL were analyzed. 18F-FDG PET/CT were performed before and after different courses of chemotherapy (60 patients in early phase which means 1 and 2 courses; 55 patients in medium phase, 3 and 4 courses; 56 patients in late phase, 5 and 6 courses). The region of interest (ROI) was drawn and the ΔSUVmax% was calculated. Patients were evaluated with Deauville 5-point scale. Fluorescence in situ hybridization (FISH) was employed to detect C-MYC gene. Patients were followed up for 6-71 months, and progression-free survival (PFS) was calculated. χ2 test, one-way analysis of variance, Kaplan-Meier analysis and Spearman correlation analysis were used to analyze the data. Results There were 42 C-MYC gene rearrangement of 171 DLBCL patients. Age, Ann Arbor stage, international prognostic index (IPI) score, serum lactate dehydrogenase (LDH) level and therapeutic response were different between patients with C-MYC gene rearrangement and those without rearrangement (χ2: 6.139-98.339, all P 0.05). Conclusion ΔSUVmax% in the different phases of chemotherapy and C-MYC gene rearrangement have better values for predicting the prognosis of DLBCL, and 18F-FDG PET/CT imaging should be performed between 1 course and 4 courses of chemotherapy. Key words: Lymphoma, large B cell, diffuse; Prognosis; Gene rearrangement; Genes, myc; Positron-emission tomography; Tomography, X-ray computed; Deoxyglucose

Diffusion-weighted MRI Is Superior to PET/CT in Predicting Survival of Patients Undergoing 90Y Radioembolization of Hepatic Metastases

Purpose To determine the relationship between diffusion-weighted (DW) liver MR images obtained 4-6 weeks after lobar yttrium 90 (90Y) treatment and overall survival in comparison with PET/CT or established oncologic factors known to affect survival. Materials and Methods The institutional review board approved this prospective intraindividual comparative study in 36 consecutive patients (25 women) with liver-dominant metastases (20 colorectal, 14 breast, two other) (mean age, 60 years ± 10 [standard deviation]) who underwent fluorine 18 (18F) fluorodeoxyglucose (FDG) PET/CT and DW MRI before and 4-6 weeks after 90Y radioembolization. DW MRI response was defined as a mean minimal apparent diffusion coefficient increase of more than 30%; PET/CT response was defined as a mean maximal standardized uptake value decrease of more than 30%. Kaplan-Meier curves, log-rank test, and multivariable Cox regression analyses were used to compare patient survival as a function of imaging and Response Evaluation Criteria in Solid Tumors (RECIST) response, pretreatment Eastern Cooperative Oncology Group (ECOG) performance status (PS) (0 vs 1), hepatic tumor load (<25% vs ≥25%), and presence versus absence of extrahepatic disease. Results Thirty-five of the 36 patients were observed until death (median survival, 36 weeks). Response was observed with PET/CT in 18 of 36 patients (50%). Median survival was 39 weeks in patients who responded to PET/CT versus 27 weeks in those who did not (P = .60). Response was observed with DW MRI in 24 of 36 patients (67%). Median survival was 53 weeks in DW MRI responders versus 20 weeks in nonresponders (P = .01). At multivariable analysis, DW MRI response was the only independent predictor of survival (P < .01). Response based on RECIST parameters, ECOG PS, hepatic tumor load, and presence of extrahepatic metastases did not correlate with survival. Conclusion In patients with hepatic metastases undergoing 90Y radioembolization, prediction of response to therapy with DW MRI was superior to that with PET/CT and established oncologic factors.

Correlation Between Standardized Uptake Value in Preneoadjuvant and Postneoadjuvant Chemoradiotherapy and Tumor Regression Grade in Patients With Locally Advanced Esophageal Cancer.

To investigate whether positron emission tomography/computed tomography (PET/CT) initial and restaging imaging predicts for pathologic response measured by tumor regression grade (TRG) after preoperative chemoradiotherapy (CRT) in patients with locally advanced esophageal cancer. A retrospective review of 220 patients with stage II-III esophageal cancer treated with neoadjuvant CRT followed by surgery was performed. In total, 187 patients were eligible for statistical analysis. Pretreatment and posttreatment PET/CT scans were reviewed. Maximum standard uptake value (SUV) at the site of the primary tumor was recorded before and 6 weeks after neoadjuvant therapy. Upon completion of surgery, TRG was determined by a specialized site-specific gastrointestinal pathologist. Spearman correlation was used to compare pre, post, and change in maximum SUV, TRG, and overall survival. The median follow-up was 24 months. Although no significant correlation was found between pretreatment SUV and TRG (r=0.073, P=0.32), post-CRT SUV, however, showed a significant positive correlation with TRG (r=0.374, P<0.01). There was no significant correlation between the absolute change in fluorodeoxyglucose uptake after CRT and TRG (r=0.057, P=0.44); however, the rate of SUV change showed a significant correlation with TRG (r=0.178, P=0.017). Similar to previous studies, our study showed a significant difference in overall survival between TRG groups (log-rank test, P=0.019). Patients with TRG 3 showed prominently worse survival with median survival of 27.4 months. Patients with favorable pathologic responses were those whose scans demonstrated a metabolic response defined as a decrease in SUV≥70%. Changes in SUV uptake on PET/CT scans after CRT have prognostic value in predicting pathologic response of esophageal cancer after neoadjuvant therapy. Further studies are needed to validate the integration of PET/CT as a decision-making tool.

Neoadjuvant Chemotherapy with Gemcitabine Plus Nab-paclitaxel Reduces the Number of Cancer-associated Fibroblasts Through Depletion of Pancreatic Stroma.

In this study, the effects of neoadjuvant chemotherapy (NAC) on cancer-associated fibroblasts (CAFs) in pancreatic cancer stroma were investigated. Density of α-smooth muscle actin (αSMA)-positive fibroblasts in resected surgical specimens from untreated patients, patients receiving conventional gemcitabine plus S-1 (GS), and patients receiving gemcitabine plus nab-paclitaxel (GnP) was determined by hybrid cell counting. 18F-Fluorodeoxyglucose positron-emission tomography (FDG-PET) scans and carbohydrate antigen 19-9 (CA19-9) concentrations were used to assess tumor activity before and after chemotherapy in the GnP group. In this retrospective study of 65 patients, αSMA expression was reduced in the GnP group, as revealed by markedly disorganized collagen and a low density of αSMA-positive fibroblasts. There were significantly fewer αSMA-positive fibroblasts in the GnP than in the untreated and GS groups, but there was no significant difference between the latter two groups. αSMA density reflected a decrease in standardized uptake value on FDG-PET, but not CA19-9 concentration, after GnP chemotherapy. These data suggest that the GnP regimen induces stromal depletion, resulting in fewer CAFs.

Importance of positron emission tomography for assessing the response of primary and metastatic lesions to induction treatments in T4 esophageal cancer

There is no consensus strategy for treatment of T4 esophageal cancer, and because of this, a better evaluation of treatment response is crucial to establish personalized therapies. This study aimed to establish a useful system for evaluating treatment response in T4 esophageal cancer. This study included 130 patients with cT4 esophageal cancer without distant metastasis who underwent 18F-fluorodeoxyglucose-positron emission tomography before and after a series of induction treatments comprising chemoradiation or chemotherapy. We evaluated the maximal standardized uptake value and treatment response. The mean±standard deviation of standardized uptake value in the primary tumor before and after induction treatments were 13.8±4.4 and 5.4±4.1, respectively, and the mean standardized uptake value decrease was 58.4%. The most significant difference in survival between positron emission tomography-primary tumor responders and nonresponders was at a decrease of 60% standardized uptake value, based on every 10% stepwise cutoff analysis (2-year cause-specific survival: 60.2 vs 23.5%; hazard ratio=2.705; P<.0001). With this cutoff value, the resectability (P=.0307), pathologic response (P=.0004), and pT stage (P<.0001) were associated with positron emission tomography-primary tumor response. Univariate analysis of 2-year cause-specific survival indicated a correlation between cause-specific survival and clinical stages according to TNMclassification, esophageal perforation, positron emission tomography-primary tumor response, lymph node status evaluated by positron emission tomography before and after induction treatments, and operative resection. Multivariate analysis further identified positron emission tomography-primary tumor response (hazard ratio=2.354; P=.0107), lymph node status evaluated by positron emission tomography after induction treatments (hazard ratio=1.966; P=.0089), and operative resection (hazard ratio=2.012; P=.0245) as independent prognostic predictors. Positron emission tomography evaluation of the response of primary and metastatic lesions to induction treatments is important to formulate treatment strategies for cT4 esophageal cancer.

Abstract 530: In vivo DVT Inflammation Presages Vein Wall Injury, and is Ameliorated by Statin Therapy

Objective: Inflammation mediates early venous thrombosis (VT) resolution and can induce vein wall scarring (VWS), a key driver of the morbid post-thrombotic syndrome (PTS). Statins exhibit anti-inflammatory properties, and may positively impact VWS after VT. However, whether early inflammation contributes to this process and can be detected is not known. In this study, we hypothesized that early VT inflammation detected by 18F-fludeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) could predict subsequent VWS and that both VT inflammation and VWS would be attenuated by statin therapy. Methods: Stasis VT was induced by complete ligation in male C57BL/6J mice (n=55) in either the infrarenal inferior vena cava (IVC, n=42) or right jugular vein (n=13). IVC VT mice were randomized to statin or control groups. Statin (rosuvastatin 5mg/kg) was given by oral gavage starting one day prior to VT induction; control mice received PBS. All mice underwent survival FDG-PET/CT venography imaging on day 2. FDG-PET inflammation signals (standard uptake value (SUV), SUVmax, target-to-background ratios (TBR)) were measured. Picrosirius red staining of day 14 VT sections measured vein wall collagen/thickness. Ex vivo VT tissue gamma counting of a subgroup was performed at day 2. Whole-thrombus protein/mRNA and VT tissue sections assessed neutrophil content. Results: FDG-PET/CT at day 2 revealed increased FDG uptake in jugular VT over the contralateral sham surgery vein (p&lt;0.001). Statin-treated mice showed a decrease in FDG-PET SUV, SUVmax and TBR (p&lt;0.05 for all). Whole-thrombus analyses and tissue section immunostaining showed reduced thrombus neutrophil content at day 2, without reducing GLUT1 or MPO expression (p&gt;0.05). At day 14, statin therapy significantly reduced VWS (p=0.02). In mice undergoing survival imaging, the day 2 FDG-PET VT inflammation signal correlated significantly with the magnitude of day 14 VWS (IVC VT r=0.74, p&lt;0.001) and jugular models of VT (r=0.62, p=0.02). Conclusions: Quantitative FDG inflammation imaging demonstrates that early VT inflammation presages subsequent VWS, and is ameliorated by prophylactic statin therapy. The overall findings support the concept that statins and could reduce VWS and PTS.

Initial results of CALGB 80803 (Alliance): A randomized phase II trial of PET scan-directed combined modality therapy for esophageal cancer.

1 Background: To determine whether changing chemotherapy (CT) during pre-op chemoradiation (CRT) based on response to induction CT by 18F-fluoro-deoxyglucose PET imaging can lead to improved pathologic complete response (pCR) in patients (pts) with resectable esophageal and gastroesophageal junction (GEJ) adenocarcinomas. Methods: 257 eligible pts were enrolled, underwent baseline PET scan, and were randomized to one of 2 induction CT arms: Modified FOLFOX-6 (oxaliplatin, leucovorin, 5-FU), days 1, 15, 29 or Carboplatin/Paclitaxel (CP), days 1, 8, 22, 29. Repeat PET was performed days 36-42; change in max standardized uptake value (SUV) from baseline was assessed. PET non-responders (≤35% decrease in SUV – PET-NR) crossed over to alternative CT regimen during CRT (50.4Gy/28 fractions). PET responders (&gt;35% decrease in SUV – PET-R) continued on same CT during CRT. Pts underwent surgery 6 wks post-CRT. Pts evaluable if had surgery, disease progression (PD), death due to disease, were unresectable or had adverse event (AE). Primary endpoint was pCR in PET-NR who crossed over to alternative CT (expected 5% under H0 to 20% under Ha). Results: Pre-audit PET response data after induction CT and pCR rates after CRT and surgery are shown in the table. For PET-NR who crossed over to alternative CT during CRT, pCR was 15.6%; 95% CI (0.08, 0.26). Conclusions: Efficacy criteria were met for an improvement in pCR rates among pts who were PET-NR after induction CT and received alternative CT during CRT for esophageal and GEJ adenoca. Pts receiving induction and concurrent CP had an unexpectedly low pCR. Support: U10CA180821, U10CA180882 Clinical trial information: NCT01333033. [Table: see text]

D38 - Prediction of tumor response after neoadjuvant chemoradiotherapy in rectal cancer using 18fluorine-2-deoxy-d-glucose positron emission tomography-computed tomography: a prospective study

Background: treatment of locally advanced rectal cancer (RC) includes pre-operative radiation therapy with chemotherapy (CRT) followed by radical surgery. The aim of this study was evaluate the role of 18fluorine-2-deoxy-D-glucose POSITRON EMISSION THOMOGRAPHY/COMPUTED TOMOGRAFY ( (18/F-FDG PET/CT) in the prediction of pathologic complete response (pCR) after CRT for rectal cancer. Material and methods: thirty-six patients (pts) ( 21 males and 15 females, age 33-84) with cT2-4 N0-2 rectal adenocarcinoma were included. This patients underwent integrated 18/F-FDG PET/CT, followed by neoadjuvant chemo-radiotherapy, PET/CT and surgery. The PET/CT results were compared with histopathological data ( Mandar's Tumor Regression Grade: TRG1 vs TRG5 as well as ypT0 N0 vs ypT1-4 N0-2. The patients were stratified according to the percentage decrease of standardized uptake values (SUV) of PET/TC: < 50% decrease, > 50% decrease and no metabolic activity. Results: All of 36 patients with PET/TC imaging before and after adjuvant chemoradiation was available. In 38 % of pts the post -CRT SUV was negative: 6 pts with pCR and TRG 1; 1 pt refused surgery; 1 pt developed liver metastasis. In 28 % of pts the post -CRT SUV decrease was > 50%: 2 pts with pCR and TRG 1, 1 pt developed lung metastasis. In 34 % of pts the post -CRT SUV decrease was < 50%: 2 pts with pCR and TRG 1, 2 pt developed lung metastasis, 1 pt developed liver metastasis and 1 pt developed brain metastasis. Conclusions: In rectal cancer PET/CT is a promising imaging marker to predict pRC to neoadjuvant theraphy.