Nano-immunoimaging.

Immunoimaging is a rapidly growing field stoked in large part by the intriguing triumphs of immunotherapy. On the heels of immunotherapy's successes, there exists a growing need to evaluate tumor response to therapy particularly immunotherapy, stratify patients into responders vs. non-responders, identify inflammation, and better understand the fundamental roles of immune system components to improve both immunoimaging and immunotherapy. Innovative nanomaterials have begun to provide novel opportunities for immunoimaging, in part due to their sensitivity, modularity, capacity for many potentially varied ligands (high avidity), and potential for multifunctionality/multimodality imaging. This review strives to comprehensively summarize the integration of nanotechnology and immunoimaging, and the field's potential for clinical applications.

Clinical utility of FDG uptake within reticuloendothelial system on F-18 FDG PET/CT for prediction of tumor recurrence in breast cancer.

BACKGROUND: The aim of this study was to investigate the metabolism of the spleen, bone marrow (BM), and liver from preoperative F-18 FDG PET/CT scans for the prediction of recurrence in breast cancer. METHODS: We retrospectively included 153 patients diagnosed with invasive ductal carcinoma (IDC) of the breast who underwent preoperative F-18 FDG PET/CT scan and a curative operation. The mean standardized uptake value (SUVmean) of the spleen, liver, and BM and maximum SUV (SUVmax) of primary tumors were measured. The relationships between spleen, BM, and liver metabolism and clinicopathologic parameters were evaluated, and possible prognostic parameters predicting recurrence were assessed using disease-free survival (DFS). RESULTS: Spleen SUVmean was significantly correlated with primary tumor SUVmax, pathologic T (pT) stage, and histologic grade of primary tumor. BM SUVmean also showed a positive correlation with primary tumor SUVmax. Spleen SUVmean were significantly associated with recurrence from binary logistic regression analysis (P = 0.004). Spleen, BM, liver, and primary tumor SUVs were all significant prognostic factors for DFS in univariate Cox regression analysis (all P<0.024). Among all PET parameters analyzed, spleen SUVmean ≥ 2.21 (P = 0.032) was in the multivariable analysis the powerful poor prognostic factor predicting DFS that was independent of other clinicopathological features like T stage (pT >2; P = 0.009) and estrogen receptor (ER) status (ER negativity; P = 0.001). CONCLUSION: Splenic metabolism together with pT stage and ER status was an independent prognostic factor for predicting recurrence in breast cancer. Metabolic activity of reticuloendothelial system such as spleen, liver or BM on preoperative F-18 FDG PET/CT can be a meritorious imaging factor for discriminating patients with IDC that require adjunctive therapy to prevent recurrence.

Reticuloendothelial system involvement in untreated sarcoidosis patients as assessed by 18F-FDG PET scanning.

Not available.

In vivo visualization of single native pancreatic islets in the mouse.

The purpose of this study was to investigate the potential of a novel targeted contrast agent (CA) for the in vivo visualization of single native pancreatic islets, the sites of insulin production, in the pancreas of mice using magnetic resonance imaging (MRI). The CA for intravenous administration was composed of the ß-cell-specific single-chain antibody fragment, SCA B1, and ferromagnetic carbon-coated cobalt nanoparticles. MRI experiments were performed at 7, 9.4 and 16.4 T in excised organs (pancreas, liver, kidney, spleen), at 7 T in mice fixed in formalin and at 9.4 and 16.4 T in living mice. Image contrast in untreated control animals was compared with images from mice treated with unspecific and specific CA. For the validation of MRI results, selected pancreases were subjected to immunohistochemical staining and numerical contrast simulations were performed. Ex vivo results and the outcome of immunohistochemistry suggest that islets are marked only by the CA containing SCA B1. Strong accumulation of particles was found also in other investigated organs owing to the uptake by the reticuloendothelial system, but the contrast in the MR images is clearly distinguishable from the islet specific contrast in pancreases and numerical predictions. In vivo experiments based on averaged dynamic sampling with 66 × 66 × 100 µm³ and triggered acquisition with 90 × 90 × 200 µm³ nominal resolution resulted in similar particle contrast to in in vitro measurements. The newly developed CA and MRI strategies have the potential to be used for studying mouse diabetes models by visualizing single native pancreatic islets.

Choline treatment affects the liver reticuloendothelial system and plasma fatty acid composition in diabetic rats.

PURPOSE: This study investigated effects of choline treatment on hepatic reticuloendothelial and biliary functions and plasma fatty acid composition in diabetic rats. METHODS: Diabetes was induced by streptozotocin (STZ). Choline was administered to untreated rats and a portion of STZ-treated rats for two sequences of five consecutive days, separated by a 2-day interval. Hepatic functions were studied using (99m) Tc Tin (II) colloid (TIN) and 99 mTc mebrofenin [bromo-iminodiacetic acid (BrIDA)] imaging. The TIN-uptake ratios (organ/whole body) of heart, liver and spleen, and the BrIDA-uptake ratios (organ or tissue/whole body) of liver, biliary tree and abdomen were obtained following imaging studies. Fatty acids were analysed by GC/MS. RESULTS: Choline treatment did not attenuate hyperglycaemic development. Diabetic rats showed (i) a decreased TIN-uptake ratio in liver with co-increased ratios in heart and spleen; choline treatment diminished these changes, (ii) elevated BrIDA-uptake ratios in biliary tree and abdomen but not in liver; choline treatment did not attenuate the elevations and (iii) decreases in plasma palmitoleic acid and oleic acid, reflecting an impaired stearoyl-CoA desaturase function; choline treatment did not affect the diminutions, but caused a decrease in arachidonic acid with a co-increase in linoleic acid. Some rats developed hypoproteinemia (HPO). HPO rats also exhibited decreases in plasma palmitoleic acid and oleic acid. Diabetes caused almost absence of palmitoleic acid in HPO rats. Choline treatment exerted no effect on the plasma fatty acid composition of diabetic HPO rats. CONCLUSIONS: Choline treatment affected hepatic reticuloendothelial function and plasma fatty acid composition, but not hepatobiliary function, in diabetic rats. Whether choline treatment is beneficial requires further studies.

Strongly magnetic iron nanoparticles improve the diagnosis of small tumours in the reticuloendothelial system by magnetic resonance imaging.

Despite advances in non-invasive medical imaging, accurate nodal staging of malignancy continues to rely on surgery. Superparamagnetic iron oxide nanoparticles (IONP) with lymphotropic qualities have shown some promise as contrast agents for MRI of the lymph nodes, but recent large-scale studies failed to show consistent detection of tumours below 5 mm. Herein we compare imaging of splenic and lymph node tissue using iron/iron oxide core/shell nanoparticles (Fe NP) that have superior magnetic qualities to IONP, to determine whether improved negative contrast in T(2)-weighted MRI can enhance the diagnosis of small tumours in the reticuloendothelial system. To provide an in vivo pre-clinical model of human lymph node micrometastases, breast cancer cells were injected into the spleens of mice, providing localised areas of tumour growth. MR images of groups of tumour-bearing and sham-treated animals were generated using a 1.5 T imaging system and analysed by two independent, blinded radiologists. Fe NP improved the sensitivity and specificity of MRI when compared to IONP, enabling accurate detection of tumours as small as 1-3 mm. The use of Fe NP as contrast agents have the potential to improve the diagnostic accuracy of MRI in cancer patients, leading to more rapid and effective treatment.

Incidental hyperdensities within the reticuloendothelial system.

This is a case report of a 79-year-old woman who was found to have numerous hyperdense nodular lesions in the upper abdomen, which were incidentally discovered during routine follow-up of a lung nodule. These hyperdense lesions included a lace-like reticular distribution within the liver, multiple extremely dense lymph nodes, and a shrunken hyperdense spleen. We discuss differential considerations for such a constellation of findings and explain why we believe the findings in this case are consistent with prior thorium dioxide exposure. We conclude with a discussion of the pathophysiology and important complications of thorium dioxide exposure and the best imaging modalities for its detection. We believe that this is an important entity that all physicians should be aware of because even though it is seldom seen today, it has characteristic imaging findings and the correct diagnosis is critical given the increased risk of malignancy for which such patients should be screened for.

Iodine-125 radiolabeling of silver nanoparticles for in vivo SPECT imaging.

Silver nanoparticles are increasingly finding applications in medicine; however, little is known about their in vivo tissue distribution. Here, we have developed a rapid method for radiolabeling of silver nanoparticles with iodine-125 in order to track in vivo tissue uptake of silver nanoparticles after systemic administration by biodistribution analysis and single-photon emission computerized tomography (SPECT) imaging. Poly(N-vinyl-2 -pyrrolidone)-capped silver nanoparticles with an average size of 12 nm were labeled by chemisorption of iodine-125 with a > 80% yield of radiolabeling efficiency. Radiolabeled silver nanoparticles were intravenously injected in Balb/c mice, and the in vivo distribution pattern of these nanoparticles was evaluated by noninvasive whole-body SPECT imaging, which revealed uptake of the nanoparticles in the liver and spleen. Biodistribution analysis confirmed predominant accumulation of the silver nanoparticles in the spleen (41.5%ID/g) and liver (24.5%ID/g) at 24 h. Extensive uptake in the tissues of the reticuloendothelial system suggests that further investigation of silver nanoparticle interaction with hepatic and splenic tissues at the cellular level is critical for evaluation of the in vivo effects and potential toxicity of silver nanoparticles. This method enables rapid iodine-125 radiolabeling of silver nanoparticles with a specific activity sufficient for in vivo imaging and biodistribution analysis.

Increased 18F-FDG uptake within the reticuloendothelial system in patients with active lung cancer on PET imaging may indicate activation of the systemic immune response.

The reticuloendothelial system (RES) cells are in the defense against certain pathogens, and in the removal of dying cells, cell debris, microorganisms, and malignant cells. Liver, spleen, and bone marrow represent the major organs with high RES activity. We hypothesized that in subjects with active lung cancer, the metabolic activity of these organs would be greater than that of the subjects with no active tumor. We have studied two groups of subjects who had undergone (18)F-FDG-PET imaging for clinical purposes. The first group consisted of 39 subjects (20 women, 19 men, mean age 64.8+/-10.2 years) with benign lung nodules as demonstrated by (18)F-FDG-PET imaging. The second group consisted of 30 subjects (18 women, 12 men; mean age 65.1+/-11 years) who were known to have active lung cancer with or without distant metastases as seen on (18)F-FDG-PET imaging. The subjects in the second group did not have any evidence of liver, spleen, bone marrow, or heart involvement on (18)F-FDG-PET images. We measured the mean SUV of the liver, spleen, bone marrow, heart, and of the contralateral unaffected lung, and compared the average SUV for these organs between the two groups. We found that the mean SUV of the liver, bone marrow, and spleen were significantly greater in subjects with evidence of active primary or metastatic lung cancer compared with those of subjects who had benign lung nodules and no evidence of active malignant disease. There was a statistically significant difference between mean SUV for organs noted above between the two groups (P<0.05). In contrast, mean SUV for the heart and contralateral normal lung did not show any significant difference between the two groups. In conclusion, the mean SUV for the major organs of RES, liver, spleen, and bone marrow were higher in subjects with active lung cancer with or without metastases than in those without active malignancy. We believe these differences in SUV may indicate a differential activation of the systemic immune response, related to the presence or absence of active lung cancer, which can be detected and quantified non-invasively through (18)F-FDG-PET imaging.

An imaging-driven model for liposomal stability and circulation.

Simultaneous labeling of the drug compartment and shell of delivery vehicles with optical and positron emission tomography (PET) probes is developed and employed to inform a hybrid physiologically based pharmacokinetic model. Based on time-dependent estimates of the concentration of these tracers within the blood pool, reticuloendothelial system (RES) and tumor interstitium, we compare the stability and circulation of long-circulating and temperature-sensitive liposomes. We find that rates of transport to the RES for long-circulating and temperature-sensitive particles are 0.046 and 0.19 h(-1), respectively. Without the application of exogenous heat, the rates of release from the long-circulating and temperature-sensitive particles circulating within the blood pool are 0.003 and 0.2 h(-1), respectively. Prolonged lifetime in circulation and slow drug release from liposomes result in a significantly greater drug area under the curve for the long-circulating particles. Future studies will couple these intrinsic parameters with exogenous heat-based release. Finally, we develop a transport constant for the transport of liposomes from the blood pool to the tumor interstitium, which is on the order of 0.01 h(-1) for the Met-1 tumor system.

[Radionuclide technique for diagnosing the mononuclear phagocytic system].

The purpose of the investigation was to determine the possibility of using colloidal radiopharmaceuticals to study the mononuclear phagocytic system in the clinical setting. The technique for studying the mononuclear phagocytic system using the labeled compounds involved the single intravenous administration of a radiolabeled colloidal solution, the registration and plotting of a change in colloid radioactivity, and the determination of radioactivity of the body as a whole and that of the lung, liver, spleen, and peritoneum. The performed investigation using colloidal radiopharmaceuticals makes it possible to study the mononuclear phagocytic system and to reveal the regularities of colloid accumulation in the organs and tissues in various diseases just in the clinical setting.

Gray scale second harmonic imaging of acoustic emission signals improves detection of liver tumors in rabbits.

This study evaluates a new reticuloendothelium specific sonographic contrast agent NC100100 (Sonazoid) for detection of liver VX-2 tumors in rabbits. Gray scale imaging of five groups of three rabbits, with hepatic VX-2 tumors implanted 7, 10, 12, 14, and 18 days previously, was performed prior to injection of Sonazoid (dosages, 0.01-0.5 ml/kg). Sonazoid produces induced acoustic emission after uptake in the liver. Therefore, harmonic gray scale images were obtained immediately after injection as well as delayed (by up to 2(1/2) h). Five rabbits (one from each group) also had angiography performed, while all animals were evaluated by pathologic examination. Non-contrast enhanced sonography detected 17 of 61 tumors (29%), as well as three false-positives, while the addition of Sonazoid detected 57 tumors (93%) and one false-positive (P<0.001). Acoustic emission made 2 x 2 mm tumors (invisible in conventional B-mode sonography) clearly perceivable in harmonic gray scale. In the subgroup that received angiography, 12 of 36 tumors (33%) were detected with conventional sonography compared to 22 tumors (61%) seen with angiography (P = 0.002). After injection of Sonazoid the ultrasonographic detection rate increased to 97% (35 of 36 tumors), which was a significant improvement over angiography (P = 0.00024). Improved detection of hepatic VX-2 tumors with second harmonic gray scale imaging of Sonazoid is possible because of this agent's acoustic emission capabilities.

Splenic function in sickle cell anemia patients in Qatif, Saudi Arabia.

A prospective study was conducted to study the splenic function among sickle cell anemia (SCA) patients in Qatif (Eastern Province of Saudi Arabia). Seventy-seven patients (30 children and 47 adults aged 2-57 years) were included. (99m)Tc stannous colloid liver-spleen scan was done for each patient during steady state. The splenic function was graded from 0 to 4 in relation to liver uptake. Seventy percent of our patients showed evidence of splenic hypofunction, and most of them (83%) had severe hyposplenism. Up to the age of 4 years, only 17% of the children showed evidence of functional hyposplenism, but by the age of 10 years >50% were hyposplenic. Most of the hyposplenic children had functional hyposplenism, whereas only one-third of hyposplenic adults had autosplenectomy. There was no effect of level of HbF on the frequency of hyposplenism, but on the other hand low MCV seems to be protective against hyposplenism. A significant number of adult SCA patients have clinically enlarged spleens, and almost a third have normally functioning spleens. Because of the low prevalence of hyposplenism in children younger than 4 years of age, routine penicillin prophylaxis is probably not indicated in this population, an issue which needs further evaluation.

Clinical applications of ultrasound contrast agents.

Within the last decade safe and practical ultrasound contrast agents have been introduced. Most of these are based on gas-filled microbubbles, which markedly enhance Doppler signals and, in some cases, also gray-scale images. The clinical improvements expected from ultrasound contrast is reviewed. Tissue-specific contrast agents constitute another area of potential clinical significance. One particular agent is taken up by the reticulo-endothelial system and produces so-called acoustic emission signals when imaged. An introduction to the unique clinical applications of acoustic emission is given. Harmonic imaging is a new contrast-specific imaging modality, which utilizes the nonlinear properties of some agents in an attempt to alleviate current limitations of ultrasound contrast studies. Examples of harmonic images are presented.

Reticuloendothelial "activation" noted after splenectomy for ITP and presence of a post-poliomyelitis asymmetry.

A radiocolloid study was carried out, after splenectomy, in a 75-year-old man who had idiopathic thrombocytopenic purpura. The patient, who did not have an increase in platelet counts after spleen removal or after platelet infusions, showed radiocolloid accumulation in the lungs and in the bone marrow. This suggested some "activation" of reticuloendothelial cells, perhaps by circulating immune complexes. The left femur (site of an episode of poliomyelitis many years previously) had less radiocolloid uptake than the right.

Magnetic resonance imaging of reticulo-endothelial system in patients with idiopathic thrombocytopenic purpura.

Idiopathic thrombocytopenic purpura (ITP) is characterized by accelerated platelet destruction in the reticulo-endothelial system (RES). We performed magnetic resonance imaging (MRI) to estimate the degree of activated RES. MRI was performed with a Gyroscan S-15 (1.5 tesla) in 7 healthy volunteers and 22 patients with ITP. The 22 patients included 19 who were at initial diagnosis or were nonresponders to the therapy (non-DX group), and 3 who were responders. For the non-DX group, the T1 relaxation time of the spleen was initially significantly shorter than for healthy volunteers, but normalized after responding to the therapy. The initially shorter T1 values of the spleen for ITP patients correlated with a low platelet count (P < 0.05). This condition may indicate foam cells or fatty components due to platelet destruction. There was no significant relationship between the sequestration in (111)In-scan and T1 values of the liver or spleen. However, MRI is a noninvasive method, and it may be a clinically useful tool in the evaluation of RES in patients with ITP.

Scintigraphic monitoring of reticuloendothelial system in patients with type 1 Gaucher disease on enzyme replacement therapy.

UNLABELLED: The purpose of this study was to define the scintigraphic pattern of marrow replacement and changes in reticuloendothelial activity after enzyme replacement therapy in patients with Gaucher disease. METHODS: Forty patients underwent baseline whole-body imaging with 99mTc-sulfur colloid and evaluation of liver and spleen volume with CT or magnetic resonance imaging. Thirty-seven of the 40 patients were treated with enzyme replacement. Therapeutic responses of central and peripheral bone marrow and the changes in pulmonary uptake of 99mTc-sulfur colloid were assessed visually at 1-4 yr after the start of therapy. Changes in liver and spleen volumes were analyzed quantitatively. The initial pattern of marrow involvement was correlated with disease severity (based on baseline blood counts and liver and spleen volumes). RESULTS: Baseline studies revealed that 38 of 40 (95%) and 28 of 40 (70%) of the patients in this study had abnormal peripheral and central marrow activity, respectively. Twenty of 24 evaluable patients (83.3%) on therapy showed regression of peripheral bone marrow activity to a more proximal location in the lower extremities, increased ratio of pelvic/proximal femoral activity to distal activity or both. Fourteen of 19 treated patients (73.7%) with abnormal initial central marrow activity showed detectable improvement in central bone marrow activity as a result of therapy. In patients with initial lung uptake of 99mTc-sulfur colloid, 91% showed complete resolution of the uptake after therapy. These changes in colloid uptake and distribution were associated with significant reductions in liver and spleen volumes and improvements in blood counts. CONCLUSION: Most patients with Gaucher disease demonstrate increased central bone marrow activity and regression of activity in peripheral bone marrow with enzyme replacement therapy. Additionally, the abnormal phagocytic pulmonary activity observed before therapy in many of the patients resolves.