Versatile and Finely Tuned Albumin Nanoplatform based on Click Chemistry.

Albumin is one of the most attractive nanoplatforms for targeted imaging and drug delivery due to its biocompatibility and long circulation half-life. However, previously reported albumin-based nanoplatforms have shown inconsistent blood circulation half-life according to the modified methods, and the affecting factors were not well evaluated, which could hamper the clinical translation of albumin-based nanoplatforms. Herein, we developed a finely tuned click-chemistry based albumin nanoplatform (CAN) with a longer circulation half-life and an efficient tumor targeting ability. Methods: CAN was synthesized in two steps. First, albumin was conjugated with ADIBO-NHS (albumin-ADIBO) by reacting albumin with various molar ratios of ADIBO. The number of attached ADIBO moieties was determined using matrix-assisted laser desorption ionization time of flight (MALDI-TOF). Second, the desired modalities including azide-functionalized chelator, a fluorescence dye, and folate were incorporated into albumin-ADIBO using strain-promoted alkyne-azide cycloaddition reaction (SPAAC reaction). The biodistribution and targeting efficiency of functionalized CANs were demonstrated in mice. Results: The degree of functionalization (DOF) and resulting in vivo biodistribution was controlled precisely using the click chemistry approach. Specifically, the numbers of attached azadibenzocyclooctyne (ADIBO) moieties on albumin, the DOF, were optimized by reacting albumin with varying molar ratios of ADIBO with a high reproducibility. Furthermore, we developed a simple and efficient method to estimate the DOF using UV-visible spectrophotometry (UV-vis), which was further validated by matrix-assisted laser desorption ionization time of flight (MALDI-TOF). The biodistribution of CAN could be controlled by DOF, and CAN with an optimized DOF showed a long circulation half-life (> 18 h). CAN was further functionalized using a simple click chemistry reaction with an azide functionalized chelator, a fluorescence dye, and folate. 64Cu- and folate-labeled CAN (64Cu-CAN-FA) showed effective and specific folate receptor targeting in vivo, with an over two-fold higher uptake than the liver at 24 h post-injection. Conclusions: Our development from the precisely controlled DOF demonstrates that an optimized CAN can be used as a multifunctional nanoplatform to obtain a longer half-life with radioisotopes and ligands, and provides an effective method for the development of albumin-based tumor theranostic agents.

Prediction of treatment outcomes in patients with chest wall sarcoma: evaluation with PET/CT.

OBJECTIVE: The aim of this study was to investigate the prognostic implications of (18)F-2-fluoro-2-deoxy-d-glucose positron emission tomography/computed tomography in patients with chest wall sarcoma. METHODS: Positron emission tomography/computed tomography scans of 42 patients (mean age: 46 years) with chest wall sarcomas were analyzed. Pathologic confirmation was obtained by surgical specimens in all patients. Tumor grade assessed by Ki-67 (MIB-1) immunohistochemical analysis and expression of glucose transporter protein 1 were compared with a maximum standardized uptake value. Univariate and multivariate analyses were conducted for estimates of overall and event-free survivals. RESULTS: The median maximum standardized uptake value of the tumor was 10.2 and the median MIB-1 index of the tumor was 32.5%. Glucose transporter protein 1 expression was found in 29 patients (69%). Univariate analyses revealed that surgery, chemotherapy, MIB-1 labeling index (cut-off 32.5%), MIB-1 grade, glucose transporter protein 1 expression and maximum standardized uptake value were possible predictors for overall and event-free survival. Multivariate analysis revealed that surgery (hazard ratio, 4.852; P = 0.017), maximum standardized uptake value (hazard ratio, 3.077; P = 0.037) and MIB-1 labeling index (hazard ratio, 6.549; P = 0.003) were independent predictors of event-free survival. In addition, surgery (hazard ratio, 4.092; P = 0.021) and maximum standardized uptake value (hazard ratio, 2.968; P = 0.027) were independent predictors of overall survival. CONCLUSIONS: (18)F-2-fluoro-2-deoxy-d-glucose positron emission tomography/computed tomography allows the prediction of prognosis after treatment in patients with chest wall sarcoma and may be useful in selecting high-risk patients for more risk-adapted treatments.

A review on the clinical uses of SPECT/CT.

In the era when positron emission tomography (PET) seems to constitute the most advanced application of nuclear medicine imaging, still the conventional procedure of single photon emission computed tomography (SPECT) is far from being obsolete, especially if combined with computed tomography (CT). In fact, this dual modality imaging technique (SPECT/CT) lends itself to a wide variety of useful diagnostic applications whose clinical impact is in most instances already well established, while the evidence is growing for newer applications. The increasing availability of new hybrid SPECT/CT devices with advanced technology offers the opportunity to shorten acquisition time and to provide accurate attenuation correction and fusion imaging. In this review we analyse and discuss the capabilities of SPECT/CT for improving sensitivity and specificity in the imaging of both oncological and non-oncological diseases. The main advantages of SPECT/CT are represented by better attenuation correction, increased specificity, and accurate depiction of the localization of disease and of possible involvement of adjacent tissues. Endocrine and neuroendocrine tumours are accurately localized and characterized by SPECT/CT, as also are solitary pulmonary nodules and lung cancers, brain tumours, lymphoma, prostate cancer, malignant and benign bone lesions, and infection. Furthermore, hybrid SPECT/CT imaging is especially suited to support the increasing applications of minimally invasive surgery, as well as to precisely define the diagnostic and prognostic profile of cardiovascular patients. Finally, the applications of SPECT/CT to other clinical disorders or malignant tumours is currently under extensive investigation, with encouraging results in terms of diagnostic accuracy.

Comparative study of FDG PET/CT and conventional imaging in the staging of rhabdomyosarcoma.

OBJECTIVE: The current study was conducted to compare the diagnostic accuracy between (18)F-fluoro-2-deoxy-D: -glucose (FDG) positron emission tomography (PET)/computed tomography (CT), and conventional imaging (CI) for the staging and re-staging of patients with rhabdomyosarcomas. METHODS: Thirty-five patients who underwent FDG PET/CT prior to treatment were evaluated retrospectively. CI methods consisted of (99m)Tc-hydroxymethylene diphosphonate bone scintigraphy, chest radiograph, whole body CT, and magnetic resonance imaging of the primary site. The images were reviewed and two boardcertified radiologists reached a diagnostic consensus. Tumor stage was confirmed by histological examination and/or follow-up examinations. RESULTS: Interpretation on the basis of FDG PET/CT, and CI, diagnostic accuracies of the T and N stages were similar. Using FDG PET/CT, the M stage was correctly assigned in 31 patients (89%), whereas the accuracy of CI in M stage was 63%. TNM stage was correctly assessed with FDG PET/CT in 30 of 35 patients (86%) and with CI in 19 of 35 patients (54%). The overall TNM staging and M staging accuracies of FDG PET/CT were significantly higher than that of CI (P < 0.01). CONCLUSIONS: FDG PET/CT is more accurate than CI regarding clinical staging and re-staging of patients with rhabdomyosarcomas.

Is the lung scan alive and well? Facts and controversies in defining the role of lung scintigraphy for the diagnosis of pulmonary embolism in the era of MDCT.

PURPOSE: The last decade has seen a changing pattern of utilization of multidetector CT (MDCT) versus lung perfusion scintigraphy in the investigation of pulmonary venous thromboembolism (VTE). In response to this the International Atomic Energy Agency (IAEA) determined that the subject required an overview. METHOD: The IAEA has invited a group of five specialists in the relevant fields to review the current status and optimum role of scintigraphy, to explore some of the facts and controversies surrounding the use of both modalities and to make recommendations about the continued role of nuclear medicine for the investigation of pulmonary embolism. This paper identifies the relative merits of each technique, highlights benefits, focuses on complementary roles and seeks a nonadversarial symbiosis. CONCLUSION: The consultants reached a consensus that the continued use of scintigraphy for diagnosis of thromboembolic disease is recommended, particularly in scenarios where scintigraphy confers specific benefits and is complementary to MDCT.

Sentinel node mapping in vulvovaginal melanoma using SPECT/CT lymphoscintigraphy.

We report 2 cases of vulvovaginal melanoma in which sentinel node mapping, performed using Tc-99m filtered sulfur colloid SPECT/CT lymphoscintigraphy, added important information to that provided by planar imaging and played a critical role in surgical planning and subsequent management. In the first case, lymphoscintigraphy planar imaging showed only foci of tracer uptake in the right groin and an equivocal focus in the left groin. SPECT/CT precisely localized these radioactive foci to the right and left inguinal sentinel nodes. The patient then underwent bilateral inguinal sentinel node sampling. In the second case, F-18 FDG PET/CT performed prior to lymphoscintigraphy demonstrated a moderately FDG-avid right inguinal lymph node that was indeterminate in nature. SPECT/CT revealed this lymph node to be a radioactive sentinel lymph node that was seen in the right groin on planar imaging. The patient then underwent right inguinal sentinel node sampling. Because pathologic study showed metastasis to the sentinel node, a planned pelvic exenteration was canceled, and the patient was referred for systemic treatment. Preoperative SPECT/CT lymphoscintigraphy is ideal for mapping the unpredicted lymphatic drainage pathways within the complex pelvic anatomy and this technique may also be used in the preoperative workup of other gynecologic malignancies.

Diagnostic performance of PET/CT in differentiation of malignant and benign non-solid solitary pulmonary nodules.

OBJECTIVE: To evaluate whether [F-18] fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT) can distinguish benign from malignant solitary pulmonary nodules (SPNs) with non-solid components. METHODS: [F-18] FDG-PET/CT scans were performed on 53 consecutive patients (30 men, 23 women; mean age 65 years) who had SPNs with non-solid components identified by CT screening for lung cancer. All patients underwent surgical resection, and all lesions were pathologically proved. Visual score, maximal, and mean standardized uptake value (SUV), and maximal and mean lesion-to-normal tissue count density ratio (LNR) were calculated in all lesions. In addition, clinical characteristics, laboratory test results, and CT findings were assessed. RESULTS: Benign SPNs with non-solid components had a higher uptake on [F-18] FDG-PET/CT. Visual score, maximal and mean SUV, and maximal and mean LNR were significantly higher in the benign when compared with the malignant SPNs (P < 0.001). When the cutoff of 1.5 was assigned for maximal SUV, the diagnostic performance of [F-18] FDG-PET/CT in predicting benign SPN revealed 100.0% sensitivity, 96.4% specificity, and 100.0% accuracy. CONCLUSIONS: [F-18] FDG-PET/CT is useful for the differential diagnosis of SPNs with non-solid components.

Correlation of chromogranin A levels and somatostatin receptor scintigraphy findings in the evaluation of metastases in carcinoid tumors.

OBJECTIVE: Chromogranin A (CgA) has been gaining acceptance as a helpful tumor marker in patients with neuroendocrine tumors, with respect to both diagnosis and prognosis. The objective of this study was to correlate serum CgA levels and somatostatin receptor scintigraphy (SRS) findings in the evaluation of metastases in carcinoid tumors. MATERIALS AND METHODS: A total of 125 patients(61 men and 64 women, aged from 23 to 84 years) with histologically diagnosed carcinoid tumor underwent serum CgA assay and SRS for detecting metastasis or disease recurrence. The quantitative determination of CgA was performed in serum using an enzyme immunoassay with a cut-off value fixed at 39 U/l. Scintigraphies were performed with 200-220 MBq of In-111-DTPA-Phel-octreotide including whole-body images as well as single-photon emission computed tomography and computed tomography scans of the chest and abdomen. RESULTS: The primary tumors originated from the gastrointestinal tract in 115 of 125 patients (92.0%), the lung in 7 of 125 patients (5.6%), the kidney in 2 of 125 patients (1.6%), and the breast in 1 of 125 patients (0.8%). The primary tumors originated from the foregut, midgut, and hindgut in 13.6%, 71.2%, and 12.8%, respectively. Correlation of SRS with other imaging modalities and clinical follow-up findings revealed a sensitivity, a specificity, and an accuracy of 82.9%, 97.7%, and 88.0%, respectively, and for CgA 62.2%, 83.7%, and 69.6%, respectively. There was 1 false-positive and 14 false-negative SRS results and 7 false-positive and 31 false-negative CgA analyses. SRS demonstrated higher sensitivity, specificity, and accuracy than CgA for the evaluation of metastatic carcinoid tumors. The concordance between SRS and CgA results was 67.2%. Discrepancies, such as positive SRS with normal CgA levels, were noted in 26 (20.8%) cases, whereas negative SRS with high CgA levels was seen in 15 (12.0%) cases. Combining the results of CgA and SRS increased the sensitivity (92.7%) but decreased the specificity (81.4%) of tumor detection. CONCLUSIONS: In our study, SRS proved to be more sensitive, more specific, and more accurate than CgA for metastatic evaluation of carcinoid tumors. Positive SRS correlated with elevation of serum CgA levels. Serum CgA might have some diagnostic utility in patients with negative SRS studies. Nevertheless, both SRS and CgA should be considered useful tools in the evaluation of metastases in carcinoid patients.