Eribulin across multiple lines of chemotherapy: a retrospective study on quality of life and efficacy in metastatic breast cancer patients.

This study evaluates efficacy, tolerability and health-related quality of life of eribulin in patients with metastatic breast cancer. Predictive and/or prognostic factors of outcome were also analyzed. Among 44 women receiving eribulin mesylate, one patient had a complete response, 22.7% a partial response and 25% a stable disease. Median overall survival and median progression-free survival were 11.8 and 4.5 months, respectively. Treatment was well tolerated; the most frequent adverse events were neutropenia (52%), leukopenia (50%), fatigue (38%) and alopecia (40%). No significant reductions of health-related quality of life parameters were observed. Disease control during previous chemotherapy lines was related with better outcome with eribulin. In conclusion, eribulin treatment should be considered in a multiple chemotherapy lines strategy in metastatic breast cancer.

Comparison between SeHCAT test and clinical response to cholestyramine in patients with chronic diarrhea and high suspicion of bile acid malabsorption: A single-center prospective study.

OBJECTIVES: We aimed to evaluate the clinical response to cholestyramine in patients with functional chronic diarrhea and a high clinical suspicion of bile-acid diarrhea (BAD) investigated with 75-selenium homocholic acid taurine (SeHCAT) test. METHODS: Adult patients attending our outpatient clinic between January and December 2021 for chronic diarrhea with suspicion of BAD were proposed SeHCAT testing and a therapeutic trial of cholestyramine 4-8 g daily. Clinical response to cholestyramine was evaluated at 1, 3, 6, and 12 months. Clinical and demographic data were analyzed according to SeHCAT test results. RESULTS: Among the 50 patients with chronic diarrhea and clinical suspicion of BAD, 13 (26.0%) refused either SeHCAT testing or cholestyramine therapy. Finally, 37 patients (31 females, age 44 ± 14 years) agreed to undergo SeHCAT and were started on cholestyramine (median follow-up 14 months [interquartile range 6-16 months]). Initial response to cholestyramine was similar in patients with positive and negative SeHCAT test results, but improved over time in those with a positive test result. Long-term response (100% vs 65.2%, P = 0.02) and necessity of maintenance therapy for symptom control were more common in those with positive SeHCAT test result (71.4% vs 26.1%, P = 0.02). However, response to cholestyramine was also frequent in patients with a negative test result. CONCLUSIONS: The SeHCAT test accurately identifies patients with BAD who benefit from long-term cholestyramine treatment. Nevertheless, cholestyramine may be also effective in patients with chronic diarrhea but negative SeHCAT test result.

A tri-modal tissue-equivalent anthropomorphic phantom for PET, CT and multi-parametric MRI radiomics.

PURPOSE: Radiomics has emerged as an advanced image processing methodology to define quantitative imaging biomarkers for prognosis and prediction of treatment response and outcome. The development of quantitative imaging biomarkers requires careful analysis to define their accuracy, stability and reproducibility through phantom measurements. Few efforts were devoted to develop realistic anthropomorphic phantoms. In this work, we developed a multimodality image phantom suitable for PET, CT and multiparametric MRI imaging. METHODS: A tissue-equivalent gel-based mixture was designed and tested for compatibility with different imaging modalities. Calibration measurements allowed to assess gel composition to simulate PET, CT and MRI contrasts of oncological lesions. The characterized gel mixture was used to create realistic synthetic lesions (e.g. lesions with irregular shape and non-uniform image contrast), to be inserted in a standard anthropomorphic phantom. In order to show phantom usefulness, issues related to accuracy, stability and reproducibility of radiomic biomarkers were addressed as proofs-of-concept. RESULTS: The procedure for gel preparation was straightforward and the characterized gel mixture allowed to mime simultaneously oncological lesion contrast in CT, PET and MRI imaging. Proofs-of-concept studies suggested that phantom measurements can be customized for specific clinical situations and radiomic protocols. CONCLUSIONS: We developed a strategy to manufacture an anthropomorphic, tissue-equivalent, multimodal phantom to be customized on specific radiomics protocols, for addressing specific methodological issues both in mono and multicentric studies.

In vivo ¹8F-FDG tumour uptake measurements in small animals using Cerenkov radiation.

PURPOSE: 2-[(18)F]Fluoro-2-deoxy-D-glucose ((18)F-FDG) is a widely used PET radiotracer for the in vivo diagnosis of several diseases such as tumours. The positrons emitted by (18)F-FDG, travelling into tissues faster than the speed of light in the same medium, are responsible for Cerenkov radiation (CR) emission which is prevalently in the visible range. The purpose of this study is to show that CR escaping from tumour tissues of small living animals injected with (18)F-FDG can be detected with optical imaging (OI) techniques using a commercial optical instrument equipped with charge-coupled detectors (CCD). METHODS: The theory behind the Cerenkov light emission and the source depth measurements using CR is first presented. Mice injected with (18)F-FDG or saline solution underwent dynamic OI acquisition and a comparison between images was performed. Multispectral analysis of the radiation was used to estimate the depth of the source of Cerenkov light. Small animal PET images were also acquired in order to compare the (18)F-FDG bio-distribution measured using OI and PET scanner. RESULTS: Cerenkov in vivo whole-body images of tumour-bearing mice and the measurements of the emission spectrum (560-660 nm range) are presented. Brain, kidneys and tumour were identified as a source of visible light in the animal body: the tissue time-activity curves reflected the physiological accumulation of (18)F-FDG in these organs. The identification is confirmed by the comparison between CR and (18)F-FDG images. CONCLUSION: These results will allow the use of conventional OI devices for the in vivo study of glucose metabolism in cancer and the assessment, for example, of anti-cancer drugs. Moreover, this demonstrates that (18)F-FDG can be employed as it is a bimodal tracer for PET and OI techniques.

Cancer-associated stroma affects FDG uptake in experimental carcinomas. Implications for FDG-PET delineation of radiotherapy target.

PURPOSE: To analyse the influence of cancer-associated stroma on FDG-uptake in two carcinoma models characterized by different stromal degrees. METHODS: Eight nude mice were subcutaneously injected with DU-145 prostate cancer cells or BXPC-3 pancreatic cancer cells, and underwent FDG-PET imaging about 2 weeks after implantation. After the mice were killed, histology, and CD31 and GLUT1 immunohistochemistry were performed. To further evaluate the highly stromalized carcinoma using perfusion-sensitive imaging, four BXPC-3 tumours underwent two successive albumin-binding (MS-325) MRI scans during tumour growth. RESULTS: FDG uptake was significantly higher in the DU-145 than in the BXPC-3 tumours, which were hardly distinguishable from adjacent normal tissue. In the BXPC-3 tumours, histology confirmed the widespread presence of aberrant infiltrated stroma, embedded with numerous vessels marked by CD31. In both tumour types, the stromal matrix was negative for GLUT1. In DU-145 tumour cells, GLUT1 immunostaining was greater than in BXPC-3 tumour cells, but not homogeneously, since it was less evident in the tumour cells which were nearer to vessels and stroma. Finally, MS-325 MRI always clearly showed areas of enhancement in the BXPC-3 tumours. CONCLUSION: Cancer-associated stroma has been reported to be capable of aerobic metabolism with low glucose consumption. Furthermore, it has been proposed that regions with high vascular perfusion exhibit a significantly lower FDG uptake, suggesting some vascular/metabolic reciprocity. Since our results are consistent with these recent findings, they signal a risk of tumour volume underestimation in radiotherapy if FDG uptake alone is used for target delineation of carcinomas, which suggests that additional evaluation should be performed using vasculature/perfusion-sensitive imaging.

Parameters Influencing PET Imaging Features: A Phantom Study with Irregular and Heterogeneous Synthetic Lesions.

Aim: To evaluate reproducibility and stability of radiomic features as effects of the use of different volume segmentation methods and reconstruction settings. The potential of radiomics in really capturing the presence of heterogeneous tumor uptake and irregular shape was also investigated. Materials and Methods: An anthropomorphic phantom miming real clinical situations including synthetic lesions with irregular shape and nonuniform radiotracer uptake was used. 18F-FDG PET/CT measurements of the phantom were performed including 38 lesions of different shape, size, lesion-to-background ratio, and radiotracer uptake distribution. Different reconstruction parameters and segmentation methods were considered. COVs were calculated to quantify feature variations over the different reconstruction settings. Friedman test was applied to the values of the radiomic features obtained for the considered segmentation approaches. Two sets of test-retest measurement were acquired and the pairwise intraclass correlation coefficient was calculated. Fifty-eight morphological and statistical features were extracted from the segmented lesion volumes. A Mann-Whitney test was used to evaluate significant differences among each feature when calculated from heterogeneous versus homogeneous uptake. The significance of each radiomic feature in terms of capturing heterogeneity was evaluated also by testing correlation with gold standard indexes of heterogeneity and sphericity. Results: The choice of the segmentation method has a strong impact on the stability of radiomic features (less than 20% can be considered stable features). Reconstruction affects the estimate of radiomic features (only 26% are stable). Thirty-one radiomic features (53%) resulted to be reproducible, 11 of them are able to discriminate heterogeneity. Among these, we found a subset of 3 radiomic features strongly correlated with GS heterogeneity index that can be suggested as good features for retrospective evaluations.

A Method for Manufacturing Oncological Phantoms for the Quantification of 18F-FDG PET and DW-MRI Studies.

The aim of this work was to develop a method to manufacture oncological phantoms for quantitation purposes in 18F-FDG PET and DW-MRI studies. Radioactive and diffusion materials were prepared using a mixture of agarose and sucrose radioactive gels. T2 relaxation and diffusion properties of gels at different sucrose concentrations were evaluated. Realistic oncological lesions were created using 3D-printed plastic molds filled with the gel mixture. Once solidified, gels were extracted from molds and immersed in a low-radioactivity gel simulating normal background tissue. A breast cancer phantom was manufactured using the proposed method as an exploratory feasibility study, including several realistic oncological configurations in terms of both radioactivity and diffusion. The phantom was acquired in PET with 18F-FDG, immediately after solidification, and in DW-MRI the following day. Functional volumes characterizing the simulated BC lesions were segmented from PET and DW-MRI images. Measured radioactive uptake and ADC values were compared with gold standards. Phantom preparation was straightforward, and the time schedule was compatible with both PET and MRI measurements. Lesions appeared on 18F-FDG PET and DW-MRI images as expected, without visible artifacts. Lesion functional parameters revealed the phantom's potential for validating quantification methods, in particular for new generation hybrid PET-MRI systems.

Restaging clear cell renal carcinoma with 18F-FDG PET/CT.

AIM: The aim of our retrospective study was to assess the usefulness of F-FDG PET/CT in the restaging of clear cell renal cell carcinoma (RCC) patients. PATIENTS AND METHODS: Sixty-nine patients (median age = 62 years; range = 36-86 years) affected by clear cell RCC (TNM at staging: T1, 42 patients; T2, 13 patients; T3, 11 patients; T4, 3 patients; Fuhrman grade: G2, 47 patients; G3, 20 patients; G4, 2 patients) underwent whole-body F-FDG PET/CT to restage the disease after nephrectomy for clinical or radiological suspicion of metastases. Areas of abnormal uptake at PET/CT were classified, taking the liver uptake as reference, as follows: 1 = faint uptake, lower than liver; 2 = moderate uptake, equal to liver; and 3 = high uptake, higher than liver. Validation of F-FDG PET/CT results was established by (1) biopsy (23 patients) and (2) other imaging modalities (addressed BS; c.e.CT; MRI; F-fluoride PET/CT; subsequent F-FDG PET/CT), and/or clinical and radiological follow-up of 12 months (46 patients). RESULTS: F-FDG PET/CT was positive in 42 patients and negative in 27 patients. Sixteen patients presented single lesions and 26 patients presented multiple localizations of the disease. On a patient basis, 40 patients resulted true positive, 2 patient false positive, 23 patients true negative, and 4 patients false negative. Sensitivity, specificity, accuracy, positive predictive value, and negative predictive value were 90%, 92%, 91%, 95%, and 85%, respectively. On a lesion basis, PET/CT detected 114 areas of abnormal uptake in 42 positive patients of which 112 resulted to be true positive. FDG uptake of the true positive lesions resulted to be high in 83 cases, moderate in 17 lesions, and finally faint in 12 lesions. CONCLUSIONS: F-FDG PET/CT demonstrated a good sensitivity in the restaging of clear cell RCC. Most of the lesions showed intense activity. According to our results, it seems that the use of F-FDG PET/CT in the restaging of RCC is feasible because the number of false-negative cases is limited.

Considerations on an automatic computed tomography tube current modulation system.

The scope of this study was to evaluate the effects on radiation output and image noise varying the acquisition parameters with an automatic tube current modulation (ATCM) system in computed tomography (CT). Chest CT examinations of an anthropomorphic phantom were acquired using a GE LightSpeed VCT 64-slice tomograph. Acquisitions were performed using different pitch, slice thickness and noise index (NI) values and varying the orientation of the scanned projection radiograph (SPR). The radiation output was determined by the CT dose index (CTDIvol). Image noise was evaluated measuring the standard deviation of CT numbers in several regions of interest. The radiation output was lower if the SPR was acquired in the anterior-posterior projection. The radiation dose with the posterior-anterior SPR was higher, because the divergence of the X-ray beam magnifies the anatomical structures closest to the tube, especially the spinal column, and this leads the ATCM system to estimate higher patient attenuation values and, therefore, to select higher tube current values. The NI was inversely proportional to the square root of the CTDIvol and, with fixed NI, the CTDIvol increased as the slice thickness decreased. This study suggests some important issues to use the GE ATCM system efficiently.

Attenuation correction for small animal PET images: a comparison of two methods.

In order to extract quantitative parameters from PET images, several physical effects such as photon attenuation, scatter, and partial volume must be taken into account. The main objectives of this work were the evaluation of photon attenuation in small animals and the implementation of two attenuation correction methods based on X-rays CT and segmentation of emission images. The accuracy of the first method with respect to the beam hardening effect was investigated by using Monte Carlo simulations. Mouse- and rat-sized phantoms were acquired in order to evaluate attenuation correction in terms of counts increment and recovery of uniform activity concentration. Both methods were applied to mice and rat images acquired with several radiotracers such as(18)F-FDG, (11)C-acetate, (68)Ga-chloride, and (18)F-NaF. The accuracy of the proposed methods was evaluated in heart and tumour tissues using (18)F-FDG images and in liver, kidney, and spinal column tissues using (11)C-acetate, (68)Ga-chloride, and (18)F-NaF images, respectively. In vivo results from animal studies show that, except for bone scans, differences between the proposed methods were about 10% in rats and 3% in mice. In conclusion, both methods provide equivalent results; however, the segmentation-based approach has several advantages being less time consuming and simple to implement.

Molecular imaging of neuroblastoma progression in TH-MYCN transgenic mice.

PURPOSE: TH-MYCN transgenic mice represent a valuable preclinical model of neuroblastoma. Current methods to study tumor progression in these mice are inaccurate or invasive, limiting the potential of this murine model. The aim of our study was to assess the potential of small animal positron emission tomography (SA-PET) to study neuroblastoma progression in TH-MYCN mice. PROCEDURE: Serial SA-PET scans using the tracer 2-deoxy-2-[(18)F]fluoro-D-glucose ((18)F-FDG) have been performed in TH-MYCN mice. Image analysis of tumor progression has been compared with ex vivo evaluation of tumor volumes and histological features. RESULTS: [(18)F]FDG-SA-PET allowed to detect early staged tumors in almost 100 % of TH-MYCN mice positive for disease. Image analysis of tumor evolution reflected the modifications of the tumor volume, histological features, and malignancy during disease progression. Image analysis of TH-MYCN mice undergoing chemotherapy treatment against neuroblastoma provided information on drug-induced alterations in tumor metabolic activity. CONCLUSIONS: These data show for the first time that [(18)F]FDG-SA-PET is a useful tool to study neuroblastoma presence and progression in TH-MYCN transgenic mice.

Feasibility of carbidopa premedication in pediatric patients: a pilot study.

AIM: To verify the potential role and feasibility of carbidopa premedication in pediatric patients undergoing ¹8F-DOPA (Fluorine-18 fluorodihydroxyphenylalanine) PET scanning. MATERIALS AND METHODS: For this limited study, 5 patients (M:F=3:2; mean age 4.8 years) with a positive history for neuroblastoma who had been referred to our institution for instrumental monitoring during clinical follow-up were enrolled. In all cases, two consecutive ¹8F-DOPA PET scans, the first without carbidopa and the second with carbidopa premedication, were scheduled: patients received 4 MBq/kg of radiotracer and a dose of 2 mg/kg of carbidopa. Dedicated VOIs were drawn on the basal ganglia, pancreas, liver, and renal cortex. These regions were semiquantitatively analyzed at both the first and at the second ¹8F-DOPA scan, and mean SUV(max) values were compared using the t-test. RESULTS: On a visual basis, a clear reduction in the abdominal accumulation of (18)F-DOPA was observed in all cases after carbidopa premedication. This reduction related both to the biliary structures and the excretory system, and was accompanied by a generalized increase in soft tissue uptake. The semiquantitative analysis documented an absolute increase in SUV(max) after carbidopa premedication in the basal ganglia (3.4±1.3 vs. 2.1±0.8) and liver parenchyma (2.2±0.5 vs. 1.5±0.5), whereas SUV(max) decreased in the renal cortex (1.7±0.8 vs. 3.7±1.0) and the pancreas (2.3±0.6 vs. 3.5±0.5). The changes in SUV(max) were statistically significant for the pancreas and liver parenchyma (p=0.022 and 0.045, respectively), but not for the basal ganglia and renal cortex (p=0.143 and 0.15, respectively). CONCLUSIONS: Carbidopa premedication in the pediatric population appears feasible and seems to influence ¹8F-DOPA distribution in the liver and pancreas in a manner similar to that reported in adults. Larger series are however needed to properly define the clinical role of carbidopa premedication in children.

Potential role of combined FDG PET/CT & contrast enhancement MRI in a rectal carcinoma model with nodal metastases characterized by a poor FDG-avidity.

PURPOSE: To investigate the additional role of MRI contrast enhancement (CE) in the primary tumor and the FDG uptake at PET in the lymph-node metastases. MATERIALS AND METHODS: A model of colorectal cancer induced by orthotopic HT-29 cells microinjection, producing pelvic lymph node metastases, was assessed using CE-MRI and FDG-PET. Histology and GLUT-1 immunohistochemistry were performed on primary tumors and iliac lymph nodes. RESULTS: Primary tumors were characterized by low FDG-uptake but high CE-MRI, particularly at tumor periphery. Undetectable FDG-uptake characterized the metastatic lymph-nodes. Histology revealed large stromal bundles at tumor periphery and a dense network of stromal fibers and neoplastic cells in the inner portion of the tumors. Both primary tumors and positive lymph nodes showed poor GLUT-1 staining. CONCLUSION: Our data support the complementary role of MRI-CE and FDG PET in some types of carcinomas characterized by abundant cancer-associated stroma and poor FDG avidity consequent to poor GLUT-1 transported. In these tumors FDG-PET alone may be not completely adequate to obtain an adequate tumor radiotherapy planning, and a combination with dual CE-MRI is strongly recommended.

Cerenkov radiation allows in vivo optical imaging of positron emitting radiotracers.

In this paper, we showed that Cerenkov radiation (CR) escaping from the surface of small living animals injected with (18)F-FDG can be detected with optical imaging techniques. (18)F decays by emitting positrons with a maximum energy of 0.635 MeV; such positrons, when travelling into tissues faster than the speed of light in the same medium, are responsible of CR emission. A detailed model of the CR spectrum considering the positron energy spectrum was developed in order to quantify the amount of light emission. The results presented in this work were obtained using a commercial optical imager equipped with charged coupled detectors (CCD). Our data open the door to optical imaging (OI) in vivo of the glucose metabolism, at least in pre-clinical research. We found that the heart and bladder can be clearly identified in the animal body reflecting the accumulation of the (18)F-FDG. Moreover, we describe two different methods based on the spectral analysis of the CR that can be used to estimate the depth of the source inside the animal. We conclude that (18)F-FDG can be employed as it is as a bimodal tracer for positron emission tomography (PET) and OI techniques. Our results are encouraging, suggesting that it could be possible to apply the proposed approach not only to beta(+) but also to pure beta(-) emitters.

Combined optical and single photon emission imaging: preliminary results.

In vivo optical imaging instruments are generally devoted to the acquisition of light coming from fluorescence or bioluminescence processes. Recently, an instrument was conceived with radioisotopic detection capabilities (Kodak in Vivo Multispectral System F) based on the conversion of x-rays from the phosphorus screen. The goal of this work is to demonstrate that an optical imager (IVIS 200, Xenogen Corp., Alameda, USA), designed for in vivo acquisitions of small animals in bioluminescent and fluorescent modalities, can even be employed to detect signals due to radioactive tracers. Our system is based on scintillator crystals for the conversion of high-energy rays and a collimator. No hardware modifications are required. Crystals alone permit the acquisition of photons coming from an in vivo 20 g nude mouse injected with a solution of methyl diphosphonate technetium 99 metastable (Tc99m-MDP). With scintillator crystals and collimators, a set of measurements aimed to fully characterize the system resolution was carried out. More precisely, system point spread function and modulation transfer function were measured at different source depths. Results show that system resolution is always better than 1.3 mm when the source depth is less than 10 mm. The resolution of the images obtained with radioactive tracers is comparable with the resolution achievable with dedicated techniques. Moreover, it is possible to detect both optical and nuclear tracers or bi-modal tracers with only one instrument.

Small animal PET for the evaluation of an animal model of genital infection.

BACKGROUND: [(18)F]-FDG is a widely used tracer for the non-invasive evaluation of hypermetabolic processes like cancer and inflammation. However, [(18)F]-FDG is considered inaccurate for the diagnosis of urinary tract and genital infections because of its urinary excretion. Since the 1970s, Gallium scintigraphy is a well established test that has been used for the evaluation of inflammation and infection in human patients. AIM: The aim of this study was to assess the feasibility of (68)Ga-Chloride small animal PET for the analysis of an animal model of genital infection, induced after the vaginal inoculum of Chlamydia muridarum. Material and Thirty mice were infected by placing 15 microl sucrose phosphate glutamic acid (SPG) 10(7) inclusion forming units of C. muridarum into the vaginal vault. As controls of inflammation, three animals were challenged with 15 microl of SPG and one healthy animal was used to assess the tracer biodistribution. Four animals died during the experiment. Eleven animals were evaluated with (68)Ga-Chloride small animal PET (GE, eXplore Vista) 3-5, 10-12, 17-19 days after infection, as well as three controls of inflammation and one healthy animal. Infection was monitored by obtaining cervical-vaginal swabs from all the animals on the day of each PET procedure. Moreover, five groups of three animals each were killed at 6, 13, 20, 27 and 34 days after infection were studied. RESULTS: (68)Ga-PET turned out positive in all the infected animals, concordantly to data obtained by the cervical swabs and by the ex vivo analysis. The tumour-to-background ratio (TBR) decreased over time as the inflammation tended to naturally extinguish. The controls showed a slightly increased uptake of tracer due to the aseptic inflammation caused by SPG and frequent cervical swabs. The healthy control did not show any pelvic uptake. CONCLUSION: (68)Ga-Chloride is a promising tracer for the assessment of genital infection in a mouse animal model.