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1.  Intratumor heterogeneity characterized by textural features on baseline 18F-FDG PET images predicts response to concomitant radiochemotherapy in esophageal cancer 
Journal of Nuclear Medicine  2011;52(3):369-378.
18F-fluorodeoxyglucose (FDG) positron emission tomography (PET) is often used in clinical routine for diagnosis, staging and response to therapy assessment or prediction. The Standardized Uptake Value (SUV) in the primary or regional area is the most common quantitative measurement derived from PET images used for those purposes. The aim of this study was to propose and evaluate new parameters obtained by textural analysis of baseline PET scans for the prediction of therapy response in esophageal cancer. Methods: 41 patients with a newly diagnosed esophageal cancer treated with combined radio-chemotherapy were included in this study. All patients underwent a pretreatment whole-body 18F-FDG PET scan. Patients were treated with radiotherapy and alkylatin-like agents (5FU-cisplatin or 5FU-carboplatin). Patients were classified as non-responders (NR: progressive or stable disease), partial-responders (PR) or complete-responders (CR) according to RECIST criteria. Different image derived indices obtained from the pretreatment PET tumor images were considered. These included usual indices such as SUVmax, SUVpeak, SUVmean, and a total of 38 features (such as for example entropy, size and magnitude of local and global heterogeneous and homogeneous tumor regions) extracted from the five different textures considered. The capacity of each parameter to classify patients with respect to response to therapy was assessed using the Kruskal-Wallis test (p-value < 0.05). Specificity and sensitivity (including 95% confidence intervals) for each of the studied parameters were derived using Receiver Operating Characteristic (ROC) curves. Results: Relationships between pairs of voxels, characterizing local tumor metabolic non-uniformities, were able to significantly differentiate all three patient groups (p<0.0006). Regional measures of tumor characteristics, such as size of non-uniform metabolic regions and corresponding intensity non-uniformities within these regions, were also significant factors for prediction to therapy (p=0.0002). ROC curve analysis showed that tumor textural analysis can provide NR, PR and CR patient identification with higher sensitivity (76%–92%) than any SUV measurement.
Textural features of tumor metabolic distribution extracted from baseline 18F-FDG PET images allow for the best stratification of esophageal carcinoma patient in the context of therapy response prediction.
PMCID: PMC3789272  PMID: 21321270
Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; therapeutic use; Carboplatin; administration & dosage; Cisplatin; administration & dosage; Combined Modality Therapy; Esophageal Neoplasms; radionuclide imaging; therapy; Female; Fluorodeoxyglucose F18; diagnostic use; Fluorouracil; administration & dosage; Humans; Image Enhancement; methods; Image Interpretation, Computer-Assisted; Male; Middle Aged; Positron-Emission Tomography; Prognosis; Radiopharmaceuticals; diagnostic use; Radiotherapy, Conformal; Reproducibility of Results; Sensitivity and Specificity; Treatment Outcome; 18F-FDG PET; esophageal cancer; texture analysis; predictive value; response to therapy
2.  Impact of tumor size and tracer uptake heterogeneity in (18)F-FDG PET and CT non-small cell lung cancer tumor delineation 
Journal of Nuclear Medicine  2011;52(11):1690-1697.
The objectives of this study were to investigate the relationship between CT and 18F-FDG PET based tumor volumes in NSCLC and the impact of tumor size and uptake heterogeneity on various PET uptake delineation approaches.
25 NSCLC cancer patients with 18F-FDG PET/CT were considered. 17 underwent surgical resection of their tumor and the maximum diameter was measured. Two observers performed manual delineation of the tumors on the CT images and delineated the tumor uptake on the corresponding PET images manually, using a fixed threshold at 50% of the maximum (T50), an adaptive threshold methodology, and the Fuzzy Locally Adaptive Bayesian (FLAB) algorithm. Maximum diameters of the delineated volumes were compared to the histopathology reference when available. The volumes of the tumors were compared, and correlation between anatomical volume, PET uptake heterogeneity and the differences between delineations were investigated.
All maximum diameters measured on PET and CT images significantly correlated with histopathology reference (r>0.89, p<0.0001). Significant differences were observed among the approaches: CT delineation resulted in large over evaluation (+32±37%), whereas all delineations on PET images resulted in under evaluation (from −15±17% for T50, to −4±8% for FLAB) except manual delineation (+8±17%). Overall, CT volumes were significantly larger than PET volumes (55±74cm3 for CT vs. from 18±25 to 47±76cm3 for PET). A significant correlation was found between the anatomical tumor size and the heterogeneity (larger lesions are more heterogeneous). Finally, the more heterogeneous was the tumor uptake, the larger the under estimation of the PET volumes by threshold-based techniques.
Volumes based on CT were larger than those defined on PET images. Tumor size and tracer uptake heterogeneity have an impact on threshold-based methods that should not be used for the delineation of large heterogeneous NSCLC, as they tend to largely underestimate the functional tumor’s spatial extent in such cases. For an accurate delineation of PET volumes in NSCLC, advanced image segmentation algorithms able to deal with tracer uptake heterogeneity should be preferred.
PMCID: PMC3482198  PMID: 21990577
Biological Transport; Carcinoma, Non-Small-Cell Lung; metabolism; pathology; radionuclide imaging; Fluorodeoxyglucose F18; diagnostic use; metabolism; Humans; Lung Neoplasms; metabolism; pathology; radionuclide imaging; Positron-Emission Tomography and Computed Tomography; methods; Radioactive Tracers; Tumor Burden; NSCLC; 18F-FDG; tumor delineation; tumor volumes; tumor size; uptake heterogeneity
3.  Impact of partial-volume effect correction on the predictive and prognostic value of baseline 18F-FDG PET images in esophageal cancer 
Journal of Nuclear Medicine  2012;53(1):12-20.
The objectives of this study were to investigate the clinical impact of partial volume effects (PVE) correction on the predictive and prognostic value of metabolically active tumor volume (MATV) measurements on 18F-FDG PET baseline scan for therapy response and overall survival in esophageal cancer patients.
50 patients with esophageal cancer treated with concomitant radio-chemotherapy between 2004 and 2008 were retrospectively considered. PET baseline scans were corrected for PVE with iterative deconvolution incorporating wavelet denoising. MATV delineation on both original and corrected images was carried out using the automatic Fuzzy Locally Adaptive Bayesian (FLAB) methodology. Several parameters were extracted considering the original and corrected images: maximum and peak SUV, mean SUV, MATV and TLG (TLG=MATV×mean SUV). The predictive value of each parameter with or without correction was investigated using Kruskal-Wallis tests and the prognostic value with Kaplan-Meier curves.
Whereas PVE correction had significant quantitative impact on the absolute values of the investigated parameters, their clinical value within the clinical context of interest was not significantly modified. This was observed for both overall survival and response to therapy. The hierarchy between parameters was the same before and after correction. SUV measurements (max, peak, mean) had non-significant (p>0.05) predictive or prognostic value, whereas functional tumor related measurements (MATV, TLG) were significant (p<0.002) predictors of response and independent prognostic factors.
PVE correction does not improve the predictive and prognostic value of baseline PET image derived parameters in esophageal cancer patients.
PMCID: PMC3477069  PMID: 22213819
Aged; Artifacts; Esophageal Neoplasms; pathology; radionuclide imaging; Female; Fluorodeoxyglucose F18; diagnostic use; Humans; Image Processing, Computer-Assisted; methods; Male; Positron-Emission Tomography; methods; Prognosis; Retrospective Studies; Tumor Burden; esophageal cancer; response to therapy; overall survival; PET; partial volume effects; SUV; tumor volume; total lesion glycolysis
4.  Baseline 18F-FDG PET image-derived parameters for therapy response prediction in oesophageal cancer 
The objectives of this study were to investigate the predictive value of tumour measurements on 18F-FDG PET pretreatment scan regarding therapy response in oesophageal cancer and to evaluate the impact of tumour delineation strategies.
50 patients with oesophageal cancer treated with concomitant radio-chemotherapy between 2004 and 2008 were retrospectively considered and classified as complete, partial or non responders (including stable and progressive disease) according to RECIST. The classification of partial and complete responders was confirmed by biopsy. Tumours were delineated on the 18F-FDG pretreatment scan using an adaptive threshold and the automatic Fuzzy Locally Adaptive Bayesian (FLAB) methodologies. Several parameters were then extracted: maximum and peak SUV, tumour longitudinal length (TL) and volume (TV), mean SUV, and Total Lesion Glycolysis (TLG=TV×mean SUV). The correlation between each parameter and response was investigated using Kruskal-Wallis tests and receiver operating characteristic methodology was used to assess performance of the parameters to differentiate patients.
Whereas commonly-used parameters such as SUV measurements were not significant predictive factors of the response, parameters related to tumour functional spatial extent (TL, TV, TLG) allowed significant differentiation of all three groups of patients, independently of the delineation strategy, and could identify complete and non responders with sensitivity above 75% and specificity above 85%. A systematic although not statistically significant trend was observed regarding the hierarchy of the delineation methodologies and the considered parameters, with slightly higher predictive value obtained with FLAB over adaptive thresholding, and TLG over TV and TL.
TLG is a promising predictive factor of concomitant radio-chemotherapy response with statistically higher predictive value than SUV measurements in advanced oesophageal cancer.
PMCID: PMC3375481  PMID: 21559979
Aged; Aged, 80 and over; Chemoradiotherapy; Esophageal Neoplasms; radionuclide imaging; therapy; Fluorodeoxyglucose F18; diagnostic use; Humans; Male; Middle Aged; Positron-Emission Tomography; Retrospective Studies; Treatment Outcome; oesophageal cancer; response to therapy; PET scan; tumour volume; total lesion glycolysis
5.  Fludarabine combined with radiotherapy in patients with locally advanced NSCLC lung carcinoma: a phase I study 
Background and purpose
Fludarabine is an adenine nucleoside analogue that has significant activity in hematological malignancies and has shown promising activity in combination with radiation in preclinical solid tumor models. We designed a phase I trial exploring concurrent fludarabine and radiotherapy in patients with advanced non-small cell lung cancer (NSCLC) to determine the maximum tolerated dose (MTD) of fludarabine given with concurrent irradiation.
Materials and methods
Thirteen patients with stage IIIB NSCLC received thoracic irradiation of 60 Gy. Fludarabine was administered during the 5th and 6th week of radiotherapy. Doses started at 10 mg/m2 per day and increased by steps of 3 mg/m2 per day.
At a daily dose of 16 mg/m2, one out of six patients developed a grade 4 leukopenia, and one a grad 3 pneumonitis. Further grade III toxicity was not observed. The dose of 13 mg/m2 was identified as the MTD. All patients developed a fludarabine dose-dependent lymphocytopenia.
Fludarabine can be safely administered concurrently with radiation at a daily dose of 13 mg/m2 during the final 2 weeks of radiotherapy. Further prospective clinical studies are required to establish the potential role of concurrent fludarabine and radiotherapy in the treatment of locally advanced inoperable NSCLC.
PMCID: PMC3605492  PMID: 22402597
Fludarabine; NSCLC; Nucleoside analogue; Concurrent fludarabine and radiotherapy; Radiotherapy, phase I study; Radiochemotherapy in stage III NSCLC, locally advanced inoperable NSCLC
6.  Epratuzumab (humanised anti-CD22 antibody) in primary Sjögren's syndrome: an open-label phase I/II study 
This open-label, phase I/II study investigated the safety and efficacy of epratuzumab, a humanised anti-CD22 monoclonal antibody, in the treatment of patients with active primary Sjögren's syndrome (pSS). Sixteen Caucasian patients (14 females/2 males, 33–72 years) were to receive 4 infusions of 360 mg/m2 epratuzumab once every 2 weeks, with 6 months of follow-up. A composite endpoint involving the Schirmer-I test, unstimulated whole salivary flow, fatigue, erythrocyte sedimentation rate (ESR), and immunoglobulin G (IgG) was devised to provide a clinically meaningful assessment of response, defined as a ≥20% improvement in at least two of the aforementioned parameters, with ≥20% reduction in ESR and/or IgG considered as a single combined criterion. Fourteen patients received all infusions without significant reactions, 1 patient received 3, and another was discontinued due to a mild acute reaction after receiving a partial infusion. Three patients showed moderately elevated levels of Human anti-human (epratuzumab) antibody not associated with clinical manifestations. B-cell levels had mean reductions of 54% and 39% at 6 and 18 weeks, respectively, but T-cell levels, immunoglobulins, and routine safety laboratory tests did not change significantly. Fifty-three percent achieved a clinical response (at ≥20% improvement level) at 6 weeks, with 53%, 47%, and 67% responding at 10, 18, and 32 weeks, respectively. Approximately 40%–50% responded at the ≥30% level, while 10%–45% responded at the ≥50% level for 10–32 weeks. Additionally, statistically significant improvements were observed in fatigue, and patient and physician global assessments. Further, we determined that pSS patients have a CD22 over-expression in their peripheral B cells, which was downregulated by epratuzumab for at least 12 weeks after the therapy. Thus, epratuzumab appears to be a promising therapy in active pSS, suggesting that further studies be conducted.
PMCID: PMC1779377  PMID: 16859536

Results 1-6 (6)