Early Assessment Of Tumor Response Research Articles

Promising drugs and treatment options for pediatric and adolescent patients with Hodgkin lymphoma.

Currently-available therapies for newly-diagnosed pediatric and adolescent patients with Hodgkin lymphoma result in >95% survival at 5years. Long-term survivors may suffer from long-term treatment-related side effects, however, so the past 20years have seen clinical trials for children and adolescents with HL gradually abandon the regimens used in adults in an effort to improve this situation. Narrower-field radiotherapy can reduce long-term toxicity while maintaining good tumor control. Various risk-adapted chemo-radiotherapy strategies have been used. Early assessment of tumor response with interim positron emission tomography and/or measuring metabolic tumor volume has been used both to limit RT in patients with favorable characteristics and to adopt more aggressive therapies in patients with a poor response. Most classical Hodgkin's lymphoma relapses occur within 3years of initial treatment, while relapses occurring 5years or more after diagnosis are rare. As the outcome for patients with relapsed/refractory classical Hodgkin lymphoma remains unsatisfactory, new drugs have been proposed for its prevention or treatment. This review summarizes the important advances made in recent years in the management of pediatric and adolescent with classical Hodgkin lymphoma, and the novel targeted treatments for relapsed and refractory classical Hodgkin lymphoma.

Early assessment of tumor response using 18F-FDG PET/CT after one cycle of systemic therapy in patients with recurrent and metastatic breast cancer.

This study was conducted to evaluate the usefulness of early assessment of tumor response using fluorine-18-fludeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) after one cycle of systemic therapy in patients with recurrent and metastatic breast cancer. Thirty-three patients with recurrent or metastatic breast cancer underwent 18F-FDG PET/CT before and after one cycle of systemic therapy. Based on the European Organization for Research and Treatment of Cancer (EORTC) criteria, the maximum standardized uptake value (SUVmax) of the same lesions (up to a total of five) noted in the baseline and follow-up scans were summed (maximum of two per organ) as target lesions, and therapeutic response was evaluated. Log-rank and Cox methods were employed to determine progression-free survival (PFS) and overall survival (OS). Complete metabolic response (CMR), partial metabolic response (PMR), stable metabolic disease (SMD), and progressive metabolic disease (PMD) was seen in 2, 16, 11, and 4 patients, respectively. The mean reduction rates of SUVmax between 84 target lesions in 18 responders (CMR/PMR) and 75 target lesions in 15 non-responders (SMD/PMD) were -55.8% (range, -100%- -1.2%) and 0.47% (range, -48.7%- +209.4%), respectively, with a significant difference (P<0.0001). Every lesion site (local lesion, lymph node metastasis, bone metastasis, lung metastasis, and liver metastasis) showed a similar tendency. Thirty patients showed progression, and 17 died due to breast cancer after a median of 38.5 months. Responders showed significantly longer PFS than non-responders (P=0.0038). Fluorine-18-FDG PET/CT after one cycle of systemic therapy was able to reflect early metabolic changes regardless of the lesion site, and showed accuracy for early response evaluation and prediction of progression in patients with recurrent or metastatic breast cancer.

Glutamate Is a Noninvasive Metabolic Biomarker of IDH1-Mutant Glioma Response to Temozolomide Treatment.

Although lower grade gliomas are driven by mutations in the isocitrate dehydrogenase 1 (IDH1) gene and are less aggressive than primary glioblastoma, they nonetheless generally recur. IDH1-mutant patients are increasingly being treated with temozolomide, but early detection of response remains a challenge and there is a need for complementary imaging methods to assess response to therapy prior to tumor shrinkage. The goal of this study was to determine the value of magnetic resonance spectroscopy (MRS)-based metabolic changes for detection of response to temozolomide in both genetically engineered and patient-derived mutant IDH1 models. Using 1H MRS in combination with chemometrics identified several metabolic alterations in temozolomide-treated cells, including a significant increase in steady-state glutamate levels. This was confirmed in vivo, where the observed 1H MRS increase in glutamate/glutamine occurred prior to tumor shrinkage. Cells labeled with [1-13C]glucose and [3-13C]glutamine, the principal sources of cellular glutamate, showed that flux to glutamate both from glucose via the tricarboxylic acid cycle and from glutamine were increased following temozolomide treatment. In line with these results, hyperpolarized [5-13C]glutamate produced from [2-13C]pyruvate and hyperpolarized [1-13C]glutamate produced from [1-13C]α-ketoglutarate were significantly higher in temozolomide-treated cells compared with controls. Collectively, our findings identify 1H MRS-detectable elevation of glutamate and hyperpolarized 13C MRS-detectable glutamate production from either pyruvate or α-ketoglutarate as potential translatable metabolic biomarkers of response to temozolomide treatment in mutant IDH1 glioma. SIGNIFICANCE: These findings show that glutamate can be used as a noninvasive, imageable metabolic marker for early assessment of tumor response to temozolomide, with the potential to improve treatment strategies for mutant IDH1 patients.

Correction: Early assessment of tumor response to photodynamic therapy using combined diffuse optical and diffuse correlation spectroscopy to predict treatment outcome.

[This corrects the article DOI: 10.18632/oncotarget.15720.].

SPECT Imaging of Treatment-Related Tumor Necrosis Using Technetium-99m-Labeled Rhein.

Noninvasive imaging of treatment-induced necrosis is important to distinguish early responders from patients resistant to the treatment plan, enabling the tailored-made therapeutic intervention. The purpose of this study was to explore the feasibility of [99mTc]EDDA-HYNIC-2C-rhein for early assessment of tumor response to treatment. In vitro necrosis avidity of [99mTc]EDDA-HYNIC-2C-rhein was evaluated in human lung cancer A549 cells treated with hyperthermia. Single photon emission-computed tomography/X-ray-computed tomography (SPECT/CT) imaging was performed in rats bearing subcutaneous W256 tumor treated with combretastatin A-4 disodium phosphate (CA4P) and rats bearing orthotopic liver W256 tumor treated with a single microwave ablation. All rats were euthanized immediately after the imaging session for biodistribution and histology studies. The mechanism of necrosis avidity for the tracer was further explored by in vivo blocking experiment and in vitro histochemistry and fluorescence staining. The uptake of [99mTc]EDDA-HYNIC-2C-rhein in necrotic cells was significantly higher than that in viable cells (p < 0.05). SPECT/CT imaging showed that an obvious "hot spot" was observed in the CA4P-treated tumor while not in the control tumor at 5h after tracer injection. Ex vivo γ-counting revealed that the uptake of [99mTc]EDDA-HYNIC-2C-rhein in tumor was increased 3.5-fold in rats treated with CA4P compared with rats treated with vehicle. Autoradiography and corresponding H&E staining suggested that the higher overall radiotracer uptake in the treated tumors was attributed to the increased necrosis. Blocking with unlabeled HYNIC-2C-rhein demonstrated the specific binding of the radiotracer to necrotic tissues. The perfect match of autoradiograph and histochemistry staining and PI fluorescence staining revealed that necrosis avidity of the tracer may be attributable to intercalation with exposed DNA in necrotic tissues. [99mTc]EDDA-HYNIC-2C-rhein can image necrosis induced by anticancer therapy and holds potential for early assessment of treatment response.

In vivo metabolic and SHG imaging for monitoring of tumor response to chemotherapy.

Although chemotherapy remains one of the main types of treatment for cancer, treatment failure is a frequent occurrence, emphasizing the need for new approaches to the early assessment of tumor response. The aim of this study was to search for indicators based on optical imaging of cellular metabolism and of collagen in tumors in vivo that enable evaluation of their response to chemotherapy. The study was performed on a mouse colorectal cancer model with the use of cisplatin, paclitaxel, and irinotecan. The metabolic activity of the tumor cells was assessed using fluorescence lifetime imaging of the metabolic cofactor reduced nicotinamide adenine dinucleotide (phosphate), NAD(P)H. Second harmonic generation (SHG) imaging was used to analyze the extent and properties of collagen within the tumors. We detected an early decrease in the free/bound NAD(P)H ratio in all treated tumors, indicating a shift toward a more oxidative metabolism. Monitoring of collagen showed an early increase in the amount of collagen followed by an increase in the extent of its orientation in tumors treated with cisplatin and paclitaxel, and decrease in collagen content in the case of irinotecan. Our study suggests that changes in cellular metabolism and fibrotic stroma organization precede morphological alterations and tumor size reduction, and that this indicates that NAD(P)H and collagen can be considered as intrinsic indicators of the response to treatment. This is the first time that these parameters have been investigated in tumors in vivo in the course of chemotherapy with drugs having different mechanisms of action. © 2018 International Society for Advancement of Cytometry.

PO-0797: Diffusion-weighted MRI for early assessment of tumor response in rectal cancer patients

PO-0797: Diffusion-weighted MRI for early assessment of tumor response in rectal cancer patients

Performance of diffusion-weighted magnetic resonance imaging at 3.0T for early assessment of tumor response in locally advanced rectal cancer treated with preoperative chemoradiation therapy.

The purpose of the article is to determine whether changes in apparent diffusion coefficient (ADC) values of locally advanced rectal cancer (LARC) obtained 2weeks after the beginning of chemoradiation therapy (CRT) allow to predict treatment response and whether correlate with tumor histopathologic response. Forty-three patients receiving CRT for LARC and 3.0T magnetic resonance imaging with diffusion-weighted sequences before treatment, 2weeks during, and 8weeks post the completion of CRT were included. ADC values were calculated at each time point and percentage of ADC changes at 2weeks (ΔADC during) and 8weeks (ΔADC post) were assessed. Data were correlated to surgical results and histopathologic tumor regression grade (TRG), according to Mandard's classification. ADC values and ΔADCs of complete responders (CR; TRG1) and non-complete responders (non-CR; TRG 2-5) were compared. Receiver-operating characteristic curve (ROC) analysis was used to assess diagnostic accuracy of ΔADC for differentiating CR from non-CR. The correlation with TRG was investigated using Spearman's rank test. ΔADC during and ΔADC post were significantly higher in CR (33.9% and 57%, respectively) compared to non-CR (13.5% and 2.2%, respectively) group (p=0.006 and p<0.001, respectively). ROC analysis revealed the following diagnostic performances: ΔADC during: AUC 0.78 (0.08), p=0.004, cut-off 20.6% (sensitivity 75% and specificity 76.5%); ΔADC post: AUC 0.94 (0.04), p≤0.001, cut-off 22% (sensitivity 95% and specificity 82.4%). Significant moderate and good negative correlation was found between ΔADC during and ΔADC post and TRG (r=-0.418, p=0.007; r=-694, p≤0.001, respectively). ΔADC at 2weeks after the beginning of CRT is a reliable tool to early assess treatment response.

Early Assessment of Tumor Response to Radiation Therapy using High-Resolution Quantitative Microvascular Ultrasound Imaging.

Measuring changes in tumor volume using anatomical imaging weeks to months post radiation therapy (RT) is currently the clinical standard for indicating treatment response to RT. For patients whose tumors do not respond successfully to treatment, this approach is suboptimal as timely modification of the treatment approach may lead to better clinical outcomes. We propose to use tumor microvasculature as a biomarker for early assessment of tumor response to RT. Acoustic angiography is a novel contrast ultrasound imaging technique that enables high-resolution microvascular imaging and has been shown to detect changes in microvascular structure due to cancer growth. Data suggest that acoustic angiography can detect longitudinal changes in the tumor microvascular environment that correlate with RT response.Methods: Three cohorts of Fisher 344 rats were implanted with rat fibrosarcoma tumors and were treated with a single fraction of RT at three dose levels (15 Gy, 20 Gy, and 25 Gy) at a dose rate of 300 MU/min. A simple treatment condition was chosen for testing the feasibility of our imaging technique. All tumors were longitudinally imaged immediately prior to and after treatment and then every 3 days after treatment for a total of 30 days. Both acoustic angiography (using in-house produced microbubble contrast agents) and standard b-mode imaging was performed at each imaging time point using a pre-clinical Vevo770 scanner and a custom modified dual-frequency transducer.Results: Results show that all treated tumors in each dose group initially responded to treatment between days 3-15 as indicated by decreased tumor growth accompanied with decreased vascular density. Untreated tumors continued to increase in both volume and vascular density until they reached the maximum allowable size of 2 cm in diameter. Tumors that displayed complete control (no tumor recurrence) continued to decrease in size and vascular density, while tumors that progressed after the initial response presented an increase in tumor volume and volumetric vascular density. The increase in tumor volumetric vascular density in recurring tumors can be detected 10.25 ± 1.5 days, 6 ± 0 days, and 4 ± 1.4 days earlier than the measurable increase in tumor volume in the 15, 20, and 25 Gy dose groups, respectively. A dose-dependent growth rate for tumor recurrence was also observed.Conclusions: In this feasibility study we have demonstrated the ability of acoustic angiography to detect longitudinal changes in vascular density, which was shown to be a potential biomarker for tumor response to RT.

Early Assessment of Tumor Response to Radiation Therapy using High-Resolution Quantitative Microvascular Ultrasound Imaging

Early Assessment of Tumor Response to Radiation Therapy using High-Resolution Quantitative Microvascular Ultrasound Imaging

Early Assessment of Tumor Response to Radiation Therapy Using High-Resolution Quantitative Microvascular Ultrasound Imaging

Tumor volume imaging several months after radiation therapy is currently used as an indicator for treatment response. For patients who did not respond well to the treatment, precious time may have been wasted as timely modification of the treatment approach may lead to better clinical outcomes. We propose to use tumor microvasculature as a biomarker for early assessment of long-term tumor response to radiation therapy. Acoustic Angiography is a novel contrast ultrasound imaging technique that enables high-resolution microvascular imaging. We aim to demonstrate that AA is capable of early prediction of long-term radiation therapy response by monitoring longitudinal changes in tumor microvasculature. Three cohorts of rats implanted with rat fibrosarcoma tumors were treated with a single dose at three dose levels. The rats were split into four different dose cohorts and received either 0 Gy (treatment control, n = 9), 15 Gy (n = 8), 20 Gy (n = 5), or 25 Gy (n = 8) radiation dose. A non-toxic FDA approved microbubble contrast agent is administrated before each ultrasound imaging by tail vein injection. Contrast enhanced ultrasound (CEUS) is a low-cost and safe imaging modality that can visualize and measure vascularity and perfusion in tissue with high contrast sensitivity compared to CT and MRI. A high-resolution microvascular imaging is performed using Acoustic Angiography, a super-harmonic CEUS imaging technique. A special ultrasound probe capable of both b-mode and Acoustic Angiography mode imaging is used and the longitudinal study lasts until 30 days post radiation. Tumor microvascular density is measured within the tumor volume defined by 3D b-mode ultrasound imaging. All tumors in each dose group responded initially (days 3-15) to treatment as indicated by decreased tumor growth accompanied with decreased vascular density. Tumors that displayed long-term control (complete response) continued to decrease in size and in vascular density. Tumors that regrew after the initial response (partial response) exhibited an increase in tumor volumetric vascular density before an increase in tumor volume. The change in tumor volumetric vascular density can be used to distinguish which animals eventually have complete control or partial control 10.25 ± 1.5 days, 9 ± 4.2 days, and 4 ± 1.4 days earlier than from the observable tumor volume change in the 15, 20, and 25 Gy dose groups, respectively. We have demonstrated the ability of a novel ultrasound tumor vascular imaging for early detection of treatment response in a preclinical study. In clinical practice, tumors often do not significantly change in size until months after treatment. Our study indicates that for some tumors we may detect non-responsive tumors 50% earlier than using the conventional RECIST method alone. By decreasing the wait time to determine treatment response doctors can make more timely modifications to treatment strategy to improve treatment outcome for individual patients.

Monitoring Daily Dynamics of Early Tumor Response to Targeted Therapy by Detecting Circulating Tumor DNA in Urine.

Purpose: Noninvasive drug biomarkers for the early assessment of tumor response can enable adaptive therapeutic decision-making and proof-of-concept studies for investigational drugs. Circulating tumor DNA (ctDNA) is released into the circulation by tumor cell turnover and has been shown to be detectable in urine.Experimental Design: We tested the hypothesis that dynamic changes in EGFR activating (exon 19del and L858R) and resistance (T790M) mutation levels detected in urine could inform tumor response within days of therapy for advanced non-small cell lung cancer (NSCLC) patients receiving osimertinib, a second-line third-generation anti-EGFR tyrosine kinase inhibitor.Results: Eight of nine evaluable NSCLC patients had detectable T790M-mutant DNA fragments in pretreatment baseline samples. Daily monitoring of mutations in urine indicated a pattern of intermittent spikes throughout week 1, suggesting apoptosis with an overall decrease in fragment numbers from baselines to day 7 preceding radiographic response assessed at 6 to 12 weeks.Conclusions: These findings suggest drug-induced tumor apoptosis within days of initial dosing. Daily sampling of ctDNA may enable early assessment of patient response and proof-of-concept studies for drug development. The modeling of tumor lysis through the day-to-day kinetics of ctDNA released into the blood and then into the urine is demonstrated in this proof-of-concept study in lung cancer patients receiving anti-EGFR tyrosine kinase inhibitors. This strategy may determine the specific clonal populations of cells which undergo apoptosis within the first week of therapy. This has important implications for developing combinational strategies to address inter- and intralesional heterogeneity and characterizing residual disease after initial drug exposure. Clin Cancer Res; 23(16); 4716-23. ©2017 AACR.

Early assessment of tumor response to photodynamic therapy using combined diffuse optical and diffuse correlation spectroscopy to predict treatment outcome.

Photodynamic therapy (PDT) of cancer involves the use of a photosensitizer that can be light-activated to eradicate tumors via direct cytotoxicity, damage to tumor vasculature and stimulating the body's immune system. Treatment outcome may vary between individuals even under the same regime; therefore a non-invasive tumor response monitoring system will be useful for personalization of the treatment protocol. We present the combined use of diffuse optical spectroscopy (DOS) and diffuse correlation spectroscopy (DCS) to provide early assessment of tumor response. The relative tissue oxygen saturation (rStO2) and relative blood flow (rBF) in tumors were measured using DOS and DCS respectively before and after PDT with reference to baseline values in a mouse model. In complete responders, PDT-induced decreases in both rStO2 and rBF levels were observed at 3 h post-PDT and the rBF remained low until 48 h post-PDT. Recovery of these parameters to baseline values was observed around 2 weeks after PDT. In partial responders, the rStO2 and rBF levels also decreased at 3 h post PDT, however the rBF values returned toward baseline values earlier at 24 h post-PDT. In contrast, the rStO2 and rBF readings in control tumors showed fluctuations above the baseline values within the first 48 h. Therefore tumor response can be predicted at 3 to 48 h post-PDT. Recovery or sustained decreases in the rBF at 48 h post-PDT corresponded to long-term tumor control. Diffuse optical measurements can thus facilitate early assessment of tumor response. This approach can enable physicians to personalize PDT treatment regimens for best outcomes.

Ultrasonic RF Time Series for Early Assessment of Tumor Response to Chemotherapy: First in Vivo Studies on Mice Breast Cancer Model

Ultrasonic RF Time Series for Early Assessment of Tumor Response to Chemotherapy: First in Vivo Studies on Mice Breast Cancer Model

US-US Fusion Imaging in Radiofrequency Ablation for Liver Metastases

Objective: Radiofrequency ablation (RFA) induces gas bubbles in ablation zones, and the ablative margin cannot be evaluated accurately on ultrasound (US) during and immediately after RFA. This study assessed the usefulness of US-US fusion imaging to visualize the ablative margin of RFA for liver metastasis. Methods: RFA guided by US-US fusion imaging was performed on 12 targeted tumors in 10 patients. Secondary hepatic malignancies included patients with colorectal cancer (n = 4), breast cancer (n = 2), lung cancer (n = 1), gastrointestinal stromal tumor (n = 1), pancreatic neuroendocrine tumor (n = 1), and adrenocortical carcinoma (n = 1). The maximal diameter of the tumors ranged from 0.8 to 4.0 cm (mean ± SD 1.6 ± 0.9 cm). Results: The mean number of electrode insertions was 1.6 per session (range 1-3). Technically, effective ablation was achieved in a single session in all patients, and safety ablative margins were confirmed on contrast-enhanced CT for early assessment of tumor response. There were no serious adverse events or procedure-related complications. During the follow-up period (median 220 days, range 31-417 days), none of the patients showed local tumor progression. Conclusion: US-US fusion imaging could show the tumor images before ablation and the ablative area on US in real time. The image overlay of US-US fusion imaging made it possible to evaluate the ablative margin three dimensionally according to the US probe action. Therefore, US-US fusion imaging can contribute to RFA therapy with a safety margin, that is, the so-called precise RFA.

Early metabolic change in (18)F-FDG-PET by measuring the single largest lesion predicts chemotherapeutic effects and patients' survival: PEACH study.

The objective of this study was to investigate the predictive value of F-18-fluorodeoxyglucose positron emission tomography (FDG-PET) for early assessment of tumor response to chemotherapy and for patient survival in gynecologic malignancies. We performed CT and FDG-PET scans before initiation of chemotherapy to determine baseline conditions. PET scan was repeated after the first cycle of chemotherapy. The tumor response was later evaluated by CT scans after three cycles of chemotherapy, using RECIST. The PET response was analyzed in terms of the difference in SUVmax for FDG of the patient's largest lesion between the baseline scan and after the first cycle of chemotherapy. The metabolic response for the tumor was defined as a 30% reduction in its SUVmax. Eleven patients received platinum-based regimens, and 20 patients received non-platinum-based regimens. The mean progression-free survival (PFS) for the patients with a metabolic response was 13 months (range 5-29). In contrast, the mean PFS of the patients with no metabolic response was only 4.3 months (range 1-18). There was a statistically significant difference between the metabolic response and PFS (p = 0.002, Mann-Whitney U test). There was a strong correlation between the metabolic response and RECIST, regardless of the chemotherapy regimens used (platinum-based group, p = 0.006; non-platinum group, p = 0.046, Fisher's exact test). The metabolic change in SUVmax was clearly predictive of tumor response in 93.5% of patients. Early FDG-PET assessment by measuring the single largest lesion is a very promising tool for rapidly predicting tumor responses and patient survival, regardless of the chemotherapy regimen.

Percutaneous fiber-optic biosensor for immediate evaluation of chemotherapy efficacy in vivo (Part I): Strategy of assay design for monitoring non-homogeneously distributed biomarkers

A fiber-optic apoptosis sensor is under development for the early assessment of tumor response to chemotherapy. It is aimed to provide bedside assessment during drug administration in differentiating treatment responses much earlier than conventional anatomical imaging techniques in tailoring the drug dosage for optimal treatment efficacy within a small therapeutic concentration window. Two fluorophores are embedded in the system for monitoring the non-homogeneously distributed apoptotic biomarker, the externalization of phosphatidylserine (PS). This manuscript introduces design concept of the 2-fluorophore assay, and summarizes the selection criteria of the 2 fluorophores, then identified the optimal exogenous fluorophores for the proposed fiber-optic apoptosis sensor from in vitro cell culture studies. FM 1-43 is the superior early apoptotic activity reporter for the in vivo monitoring fiber-optic sensor compared with the more widely commercialized annexin V-FITC, because it can provide superior sensitivity and specificity for the fiber-optic measurements with capability in potential needs of sequential detections. As a cell spatial distribution indicator (for calibrating the geometrical effect of the non-homogeneously distributed biomarkers on the detected fluorescent signal), phospholipid conjugated marina blue can provide timely quantifiable values indicating only cell densities (spatial distribution index), regardless of the treatment of the apoptotic initiator, without interfering the optical characteristics of FM 1-43 in indicating apoptotic activity. The bioanalytical performance of the sensor in identifying drug-induced apoptosis with the 2-fluorophore assay is assessed (in vitro and in vivo) in another manuscript (for further details see [19]).

Preclinical assessment of early tumor response after irradiation by positron emission tomography with 2-amino-[3-¹¹C]isobutyric acid.

The positron emission tomography (PET) probe, 2-amino-[3-¹¹C]isobutyric acid ([3-¹¹C]AIB), is reported to accumulate less in inflammatory lesions than 2-deoxy-2-[¹⁸F]fluoro-D-glucose ([¹⁸F]FDG) and has the potential for evaluation of the efficacy of radiotherapy. To determine whether [3-¹¹C]AIB is useful to monitor early metabolic change in tumors after radiotherapy, we evaluated the temporal change in [3-¹¹C]AIB tumor uptake, tumor volume, histological features and expression of amino acid transporters early after radiotherapy in a mouse tumor model. PET with [3-¹¹C]AIB was conducted in mice bearing a subcutaneous tumor (SY, derived from small cell lung cancer) in two schedules: schedule 1, before (day -1) and after (days 1 and 3) 15 Gy of radiation and schedule 2, days -1, 1 and 5. [3-¹¹C]AIB tumor uptake tended to increase on day 1 after irradiation and decreased thereafter. Tumor uptake was not correlated with tumor volume in schedule 1. Although tumor uptake was correlated with tumor volume in schedule 2, this correlation was lost when the day 5 data of greatly reduced tumor volumes were excluded. In a separate group of tumor-bearing mice, excised tumor sections were stained with terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling (TUNEL) or anti-Ki-67 antibody. There was no correlation between tumor uptake and percentages of TUNEL- or Ki-67-positive cells. Expression of amino acid transporters, SLC38A1, SLC38A2 and SLC38A4, was determined by real-time RT-PCR. SLC38A1 and SLC38A2 were expressed in SY tumors, and a significant correlation was observed between [3-¹¹C]AIB tumor uptake and SLC38A1 expression. In conclusion, early change in [3-¹¹C]AIB tumor uptake after irradiation reflected the temporal change in amino acid transporter expression, while it was independent of change in tumor volume, apoptosis and cell proliferation. PET with [3-¹¹C]AIB has the potential for use in non-invasive evaluation of early metabolic change after irradiation before morphological change of tumors.

Tumor Hypoxia Response After Targeted Therapy in EGFR-Mutant Non-Small Cell Lung Cancer: Proof of Concept for FMISO-PET.

Hypoxia is associated with resistance to radiotherapy and chemotherapy. Functional imaging of hypoxia in non-small cell lung cancer (NSCLC) could allow early assessment of tumor response and guide subsequent therapies. Epidermal growth factor receptor (EGFR) inhibition with erlotinib reduces hypoxia in vivo. [18F]-Fluoromisonidazole (FMISO) is a radiolabeled tracer that selectively accumulates in hypoxic cells. We sought to determine whether FMISO positron emission tomography (FMISO-PET) could detect changes in hypoxia in vivo in response to EGFR-targeted therapy. In a preclinical investigation, nude mice with human EGFR-mutant lung adenocarcinoma xenografts underwent FMISO-PET scans before and 5 days after erlotinib or empty vehicle initiation. Descriptive statistics and analysis of variance (ANOVA) tests were used to analyze changes in standardized uptake value (SUV), with pooled analyses for the mice in each group (baseline, postvehicle, and posterlotinib). In a small correlative pilot human study, patients with EGFR-mutant metastatic NSCLC underwent FMISO-PET scans before and 10 to 12 days after erlotinib initiation. Changes in SUV were compared to standard chest computed tomography (CT) scans performed 6 weeks after erlotinib initiation. The mean (±standard error of the mean; SUVmean) of the xenografts was 0.17 ± 0.014, 0.14 ± 0.008, and 0.06 ± 0.004 for baseline, postvehicle, and posterlotinib groups, respectively, with lower SUVmean among the posterlotinib group compared to other groups (P < .05). Changes on preclinical PET imaging were striking, with near-complete disappearance of FMISO uptake after erlotinib initiation. Two patients were enrolled on the pilot study. In the first patient, SUVmean increased by 21% after erlotinib, with progression on 6-week chest CT followed by death after 4.8 months. In the second patient, SUVmean decreased by 7% after erlotinib, with regression on 6-week chest CT accompanied by clinical improvement; the patient had stable disease at 14.5 months. In conclusion, we observed that FMISO-PET can detect changes in hypoxia levels after EGFR-directed therapy in EGFR-mutant NSCLC. Further study is warranted to determine its utility as an imaging biomarker of early response to EGFR-directed therapy.

Diffusion-weighted MRI in early assessment of tumour response to radiotherapy in high-risk prostate cancer.

The objective of this study was to assess the efficacy of diffusion-weighted MRI (DWI) in monitoring response to radiotherapy in high-risk prostate cancer (PC). This retrospective study included 78 patients with high-risk PC undergoing 3.0-T MRI (supplemented by DWI) before and after intensity-modulated radiotherapy (IMRT). Based on follow-up clinical examinations, patients were divided into two groups: the recurrence group (patients who suffered biochemical/clinical recurrence within 3 years, n = 13) and the non-recurrence group (patients who were recurrence free for over 3 years, n = 65). The apparent diffusion coefficient (ADC) values before and after IMRT were compared between these two groups. The receiver-operating characteristics (ROC) analysis was carried out to investigate the discriminatory capability for pre- and post-IMRT ADC values. The overall ADC values were 1.04 ± 0.18 × 10(-3) mm(2) s(-1) for PCs before IMRT and 1.45 ± 0.15 × 10(-3) mm(2) s(-1) after IMRT (p < 0.001). A statistically significant difference in post-IMRT ADC values was noted between patients with and without recurrence (1.27 ± 0.14 × 10(-3) mm(2) s(-1) vs 1.49 ± 0.12 × 10(-3)mm(2) s(-1); p < 0.001), although there was no statistical difference between them in pre-IMRT ADC values (1.00 ± 0.17 × 10(-3) mm(2) s(-1) vs 1.05 ± 0.18 × 10(-3) mm(2) s(-1); p = 0.31). The ROC curve analysis revealed that the post-IMRT ADC values could help identify patients suffering recurrences (area under the curve, 0.88; p < 0.001). Marked increase in ADC values was observed in PC after radiotherapy, especially in good responders. DWI is a valuable tool for monitoring the response to radiotherapy. This study examined the relationship between ADC changes and tumour response to treatment of PC.