Xiaorong Sun

Value of PET/CT versus enhanced CT for locoregional lymph nodes in non-small cell lung cancer ☆

PURPOSE To compare the diagnostic efficacies of integrated (18)F FDG PET/CT images and contrast-enhanced helical CT images in locoregional lymph node metastasis in the patients with non-small cell lung cancer (NSCLC). METHODS From June 2005 to June 2007, 122 potentially operable patients with proven or suspected non-small cell lung cancer underwent integrated PET/CT and contrast-enhanced CT scans followed by surgical nodal staging. The results of reviewing PET/CT and enhanced CT images for the locoregional lymph node metastasis were compared in relation to pathologic findings. RESULTS Preoperative nodal staging was compared with postoperative histopathological staging, 80% (98 of 122) of patients correctly staged, 13% (16 of 122) of patients were overstaged, and 7% (8 of 122) were understaged by PET/CT, while those values for CT were 56% (68 of 122), 26% (32 of 122), and 18% (22 of 122), respectively. The sensitivity, specificity, accuracy, positive predictive value, and negative predictive value of PET/CT for lymph nodes were 86%, 85%, 85%, 64%, 95%, respectively; compared with 69%, 71%, 70%, 43%, 88% for CT (P=0.000, 0.000, 0.000, 0.001, 0.001, respectively). 81% false-negative interpretations and 72% false-positive interpretations on CT were corrected by PET/CT. 57% false-negative interpretations and 45% false-positive interpretations on PET/CT were corrected by CT. 6 % (9 of 153) positive lymph nodes and 8% (40 of 486) negative nodes at pathology were incorrectly diagnosed both by PET/CT and CT. CONCLUSION Integrated PET/CT improves the sensitivity, specificity, accuracy, positive predictive value, and negative predictive value than enhanced CT in the assessment of locoregional lymph nodes, and provides more efficient and accurate data of nodal staging, with a better effect on diagnosis and therapy in non-small cell lung cancer.

Comparison of Tumor Volumes as Determined by Pathologic Examination and FDG-PET/CT Images of Non–Small-Cell Lung Cancer: A Pilot Study

PURPOSE To determine the cut-off standardized uptake value (SUV) on (18)F fluoro-2-deoxy-glucose (FDG) positron emission tomography/computed tomography (FDG-PET/CT) images that generates the best volumetric match to pathologic gross tumor volume (GTV(path)) for non-small-cell lung cancer (NSCLC). METHODS AND MATERIALS Fifteen patients with NSCLC who underwent FDG-PET/CT scans followed by lobectomy were enrolled. The surgical specimen was dissected into 5-7-mum sections at approximately 4-mm intervals and stained with hematoxylin and eosin. The tumor-containing area was outlined slice by slice and the GTV(path) determined by summing over all the slices, taking into account the interslice thickness and fixation-induced volume reduction. The gross tumor volume from the PET images, GTV(PET), was determined as a function of cut-off SUV. The optimal threshold or optimal absolute SUV was defined as the value at which the GTV(PET) was the same as the GTV(path). RESULTS The fixation process induced a volumetric reduction to 82% +/- 10% (range, 62-100%) of the original. The maximal SUV was 10.1 +/- 3.6 (range, 4.2-18.7). The optimal threshold and absolute SUV were 31% +/- 11% and 3.0 +/- 1.6, respectively. The optimal threshold was inversely correlated with GTV(path) and tumor diameter (p < 0.05), but the optimal absolute SUV had no significant correlation with GTV(path) or tumor diameter (p > 0.05). CONCLUSION This study evaluated the use of GTV(path) as a criterion for determining the optimal cut-off SUV for NSCLC target volume delineation. Confirmatory studies including more cases are being performed.

Noninvasive Molecular Imaging of Hypoxia in Human Xenografts: Comparing Hypoxia-Induced Gene Expression with Endogenous and Exogenous Hypoxia Markers

Tumor hypoxia is important in the development and treatment of human cancers. We have developed a novel xenograft model for studying and imaging of hypoxia-induced gene expression. A hypoxia-inducible dual reporter herpes simplex virus type 1 thymidine kinase and enhanced green fluorescence protein (HSV1-TKeGFP), under the control of hypoxia response element (9HRE), was stably transfected into human colorectal HT29 cancer cells. Selected clones were further enriched by repeated live cell sorting gated for hypoxia-induced eGFP expression. Fluorescent microscopy, fluorescence-activated cell sorting, and radioactive substrate trapping assays showed strong hypoxia-induced expression of eGFP and HSV1-tk enzyme in the HT29-9HRE cells in vitro. Sequential micropositron emission tomography (PET) imaging of tumor-bearing animals, using the hypoxic cell tracer (18)F-FMISO and the reporter substrate (124)I-FIAU, yielded similar tumor hypoxia images for the HT29-9HRE xenograft but not in the parental HT29 tumor. Using autoradiography and IHC, detailed spatial distributions in tumor sections were obtained and compared for the following hypoxia-associated biomarkers in the HT29-9HRE xenograft: (124)I-FIAU, (18)F-FMISO, Hoechst (perfusion), lectin-TRITC (functional blood vessels), eGFP, pimonidazole, EF5, and CA9. Intratumoral distributions of (124)I-FIAU and (18)F-FMISO were similar, and eGFP, pimonidazole, EF5, and CA9 colocalized in the same areas but not in well-perfused regions that were positive for Hoechst and lectin-TRITC. In enabling the detection of hypoxia-induced molecular events and mapping their distribution in vivo with serial noninvasive positron emission tomography imaging, and multiple variable analysis with immunohistochemistry and fluorescence microscopy, this human xenograft model provides a valuable tool for studying tumor hypoxia and in validating existing and future exogenous markers for tumor hypoxia.

Imaging of proliferation with 18F-FLT PET/CT versus 18F-FDG PET/CT in non-small-cell lung cancer

PurposeTo compare the diagnostic efficacies of 18F-FLT and 18F-FDG PET/CT in non-small-cell lung cancer (NSCLC), focusing on the correlation between FLT and FDG tumour uptake and tumour cell proliferation as indicated by the cyclin D1 labelling index.MethodsA total of 31 patients with NSCLC underwent FLT and FDG PET/CT scanning followed by surgery. PET/CT images were compared with the pathology. Tumour cell proliferation was assessed by cyclin D1 immunohistochemistry.ResultsThe sensitivities of FLT and FDG PET/CT for the primary lesion were 74% and 94%, respectively (p=0.031). For N staging, 77% patients were correctly staged, 6% overstaged, 16% understaged by FLT, while the values for FDG were 77%, 16% and 6%, respectively. The sensitivity, specificity, accuracy, and positive predictive value with FLT for lymph nodes were 65%, 98%, 93% and 89%, respectively, and 85%, 84%, 84% and 52% with FDG (p<0.01).Tumour SUV of FLT was significantly correlated with the cyclin D1 labelling index (r=0.644; p<0.01), but the SUV of FDG was not significantly correlated (r=0.293; p>0.05).ConclusionIn terms of N staging, FLT PET/CT resulted in understaging of more patients but overstaging of fewer patients, and for regional lymph nodes showed better specificity, accuracy and positive predictive value than FDG PET/CT in NSCLC. Tumour FLT uptake was correlated with tumour cell proliferation as indicated by the cyclin D1 labelling index, suggesting that further studies are needed to evaluate the use of FLT PET/CT for the assessment of therapy response to anticancer drugs.

Changes in tumor hypoxia induced by mild temperature hyperthermia as assessed by dual-tracer immunohistochemistry

PURPOSE To study the changes in hypoxia resulting from mild temperature hyperthermia (MTH) in a subcutaneous xenograft model using dual-tracer immunohistochemical techniques. MATERIALS AND METHODS HT29 tumors were locally heated at 41 degrees C. Changes in tumor hypoxia were investigated by pimonidazole and EF5. Pimonidazole was given 1h preheating, EF5 at various times during or after treatment, 1h later the animals were sacrificed. Blood vessels were identified by CD31 staining, and perfusion by Hoechst 33342 injected 1 min pre-sacrifice. RESULTS The overall hypoxic fraction was significantly decreased by MTH during and immediately after heating. However, MTH induced both increases and decreases in tumor hypoxia in different parts of the tumor. Specifically, MTH decreased hypoxia in the regions with relatively well-perfused blood vessels, but increased hypoxia in regions that were poorly perfused. At 24-h post heating, newly formed hypoxic regions surrounded previously-hypoxic foci, which in turn surrounded pimonidazole-stained debris. Quantitative analysis did not evince changes in tumor oxygenation due to MTH at 24h post-treatment. CONCLUSION In this xenograft model, the effect of MTH on tumor oxygenation was variable, both spatially and kinetically. Overall tumor oxygenation was improved during and after heating, but the effect was short-lived.

The effect of mild temperature hyperthermia on tumour hypoxia and blood perfusion: relevance for radiotherapy, vascular targeting and imaging.

Clinically achievable mild temperature local hyperthermia (<43°C) has been demonstrated to be an effective adjuvant to radiotherapy in pre-clinical and clinical studies. In this article, we briefly review the recent progress in the following areas: (1) the effect of mild temperature hyperthermia (MTH) on tumour hypoxia and blood perfusion as assessed by dual marker immunohistochemistry (IHC); (2) the kinetics of MTH induced changes in tumour hypoxia; (3) the potential role of heat-induced tumour reoxygenation on radio- and chemo-sensitisation; (4) the potential role of MTH in combination with vascular targeting agents (VTAs) on tumour response; and (5) non-invasive detection of changes in tumour oxygenation and blood perfusion. It is shown that MTH, by itself or in combination with VTAs, leads to changes in tumour perfusion and oxygenation with potential for radio- and chemo-sensitisation.

Prognostic significance of SUV on PET/CT in patients with localised oesophagogastric junction cancer receiving neoadjuvant chemotherapy/chemoradiation: a systematic review and meta-analysis

OBJECTIVE The objective of this study was to comprehensively review the evidence for use of pre-treatment, post-treatment and changes in tumour glucose uptake that were assessed by 18-fludeoxyglucose ((18)F-FDG) positron emission tomography (PET) early, during or immediately after neoadjuvant chemotherapy/chemoradiation to predict prognosis of localised oesophagogastric junction (AEG) cancer. METHODS We searched for articles published in English; limited to AEG; (18)F-FDG uptake on PET performed on a dedicated device; dealt with the impact of standard uptake value (SUV) on survival. We extracted an estimate of the log hazard ratios (HRs) and their variances and performed meta-analysis. RESULTS 798 patients with AEG were included. And the scan time for (18)F-FDG-PET was as follows: prior to therapy (PET1, n=646), exactly 2 weeks after initiation of neoadjuvant therapy (PET2, n=245), and pre-operatively (PET3, n=278). In the two meta-analyses for overall survival, including the studies that dealt with reduction of tumour maximum SUV (SUV(max)) (from PET1 to PET2/PET3 and from PET1 to PET2), the results were similar, with the overall HR for non-responders being 1.83 [95% confidence interval (CI), 1.41-2.36] and 2.62 (95% CI, 1.61-4.26), respectively; as for disease-free survival, the combined HR was 2.92 (95% CI, 2.08-4.10) and 2.39 (95% CI, 1.57-3.64), respectively. The meta-analyses did not attribute significant prognostic values to SUV(max) before and during therapy in localised AEG. CONCLUSION Relative changes in FDG-uptake of AEG are better prognosticators. Early metabolic changes from PET1 to PET2 may provide the same accuracy for prediction of treatment outcome as late changes from PET1 to PET3.

High 18F-FDG Uptake in Microscopic Peritoneal Tumors Requires Physiologic Hypoxia

The objective of this study was to examine 18F-FDG uptake in microscopic tumors grown intraperitoneally in nude mice and to relate this to physiologic hypoxia and glucose transporter-1 (GLUT-1) expression. Methods: Human colon cancer HT29 and HCT-8 cells were injected intraperitoneally into nude mice to generate disseminated tumors of varying sizes. After overnight fasting, animals, breathing either air or carbogen (95% O2 + 5% CO2), were intravenously administered 18F-FDG together with the hypoxia marker pimonidazole and cellular proliferation marker bromodeoxyuridine 1 h before sacrifice. Hoechst 33342, a perfusion marker, was administered 1 min before sacrifice. After sacrifice, the intratumoral distribution of 18F-FDG was assessed by digital autoradiography of frozen tissue sections. Intratumoral distribution was compared with the distributions of pimonidazole, GLUT-1 expression, bromodeoxyuridine, and Hoechst 33342 as visualized by immunofluorescent microscopy. Results: Small tumors (diameter, <1 mm) had high 18F-FDG accumulation and were severely hypoxic, with high GLUT-1 expression. Larger tumors (diameter, 1–4 mm) generally had low 18F-FDG accumulation and were not significantly hypoxic, with low GLUT-1 expression. Carbogen breathing significantly decreased 18F-FDG accumulation and tumor hypoxia in microscopic tumors but had little effect on GLUT-1 expression. Conclusion: There was high 18F-FDG uptake in microscopic tumors that was spatially associated with physiologic hypoxia and high GLUT-1 expression. This enhanced uptake was abrogated by carbogen breathing, indicating that in the absence of physiologic hypoxia, high GLUT-1 expression, by itself, was insufficient to ensure high 18F-FDG uptake.

Assessment of 11C-labeled-4-N-(3-bromoanilino)-6, 7-dimethoxyquinazoline as a positron emission tomography agent to monitor epidermal growth factor receptor expression

The aim of the present study was to investigate the biodistribution of 11C‐labeled‐4‐N‐(3‐bromoanilino), 6,7‐dimethoxyquinazoline (11C‐PD153035) and the relationship between accumulation of the tracer and epidermal growth factor receptor (EGFR) expression levels. Biodistribution studies of 11C‐PD153035 were performed in tumor‐bearing nude mice. The amount of radioactivity in the lungs was small while concentrations were highest in the liver and intestine. From in vitro studies, the level of 11C‐PD153035 accumulation was detected in MDA‐MB‐468, A549, and MDA‐MB‐231 cells. The uptake of 11C‐PD153035 in cells was closely correlated with the EGFR expression level of cells (r2 = 0.85; P < 0.001), and the results obtained in excised tumors were also significantly correlated (r2 = 0.63; P = 0.003). Binding in MDA‐MB‐468, A549, and MDA‐MB‐231 tumors was reduced to background level at 60 min post injection 11C‐PD153035 by pretreatment with cold PD153035. The present study showed that whether in vitro or ex vivo the uptake of 11C‐PD153035 closely correlated with EGFR expression levels. In contrast, blocking studies revealed specific binding in the three kinds of tumors. Thus 11C‐PD153035 may be used as a positron emission tomography tracer to yield useful information about tumors, particularly for lung cancer with different EGFR expression levels. (Cancer Sci 2007; 98: 1413–1416)

Phase I study of topical epigallocatechin-3-gallate (EGCG) in patients with breast cancer receiving adjuvant radiotherapy

OBJECTIVE The purpose of this study was to investigate the safety, tolerability and preliminary effectiveness of topical epigallocatechin-3-gallate (EGCG) for radiation dermatitis in patients with breast cancer receiving adjuvant radiotherapy. METHODS Patients with breast cancer who received radiotherapy to the chest wall after mastectomy were enrolled. EGCG solution was sprayed to the radiation field from the initiation of Grade 1 radiation dermatitis until 2 weeks after completion of radiotherapy. EGCG concentration escalated from 40 to 660 μmol l(-1) in 7 levels with 3-6 patients in each level. EGCG toxicity was graded using the NCI (National Cancer Institute Common Terminology Criteria for Adverse Events) v. 3.0. Any adverse event >Grade 1 attributed to EGCG was considered dose-limiting toxicity. The maximum tolerated dose was defined as the dose level that induced dose-limiting toxicity in more than one-third of patients at a given cohort. Radiation dermatitis was recorded weekly by the Radiation Therapy Oncology Group scoring and patient-reported symptoms. RESULTS From March 2012 to August 2013, 24 patients were enrolled. Acute skin redness was observed in 1 patient and considered to be associated with the EGCG treatment at 140 μmol l(-1) level. Three more patients were enrolled at this level and did not experience toxicity to EGCG. The dose escalation stopped at 660 μmol l(-1). No other reported acute toxicity was associated with EGCG. Grade 2 radiation dermatitis was observed in eight patients during or after radiotherapy, but all decreased to Grade 1 after EGCG treatments. Patient-reported symptom scores were significantly decreased at 2 weeks after the end of radiotherapy in pain, burning, itching and tenderness, p < 0.05. CONCLUSION The topical administration of EGCG was well tolerated and the maximum tolerated dose was not found. EGCG may be effective in treating radiation dermatitis with preliminary investigation. ADVANCES IN KNOWLEDGE EGCG solution seemed to be feasible for treating radiation dermatitis in patients with breast cancer after mastectomy. It should be tested as a way to reduce radiation-induced normal tissue toxicity and complications in future years.