Recent advances in immune modulation have made impressive progress in cancer immunotherapy. Because dynamic nature of the immune response often makes it difficult to evaluate therapeutic outcomes, innovative imaging technologies have been developed to enable non-invasive visualization of immune cells and tumors in their microenvironment. This review summarizes the current tumor immunology and describes new innovative imaging methods with great potential to obtain non-invasive real-time insights into the complex functions of the immune system and into the management of cancer immunotherapy.

Purpose: A near-infrared (NIR) fluorescence imaging is a promising tool for cancer-specific image guided surgery. Human epidermal receptor 2 (HER2) is one of the candidate markers for gastric cancer. In this study, we aimed to synthesize HER2-specific NIR fluorescence probes and evaluate their applicability in cancer-specific image-guided surgeries using an animal model. Materials and Methods: An NIR dye emitting light at 800 nm (IRDye800CW; Li-COR) was conjugated to trastuzumab and an HER2-specific affibody using a click mechanism. HER2 affinity was assessed using surface plasmon resonance. Gastric cancer cell lines (NCI-N87 and SNU-601) were subcutaneously implanted into female BALB/c nu (6–8 weeks old) mice.After intravenous injection of the probes, biodistribution and fluorescence signal intensity were measured using Lumina II (Perkin Elmer) and a laparoscopic NIR camera (InTheSmart). Results: Trastuzumab-IRDye800CW exhibited high affinity for HER2 (KD =2.093(3) pM).Fluorescence signals in the liver and spleen were the highest at 24 hours post injection, while the signal in HER2-positive tumor cells increased until 72 hours, as assessed using the Lumina II system. The signal corresponding to the tumor was visually identified and clearly differentiated from the liver after 72 hours using a laparoscopic NIR camera. AffibodyIRDye800CW also exhibited high affinity for HER2 (KD =4.71 nM); however, the signal was not identified in the tumor, probably owing to rapid renal clearance. Conclusions Trastuzumab-IRDye800CW may be used as a potential NIR probe that can be injected 2–3 days before surgery to obtain high HER2-specific signal and contrast. Affibodybased NIR probes may require modifications to enhance mobilization to the tumor site.

In order to develop a successful vaccine against deadly diseases with a wide range of antigenic diversity, an in-depth knowledge of the molecules and signaling mechanisms between the vaccine candidates and immune cells is required. Therefore, monitoring vaccine components, such as antigen or adjuvants, and immune cell dynamics at the vaccination site or draining lymph nodes can provide important information to understand more about the vaccine response. This review briefly introduces and describes various non-invasive molecular imaging methods for visualizing immune cell dynamics after vaccination.
Antigenic Variation ; Lymph Nodes ; Molecular Imaging ; Vaccination ; Vaccines

BACKGROUND/AIMS: This study analyzed the diagnostic accuracy of endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) for pancreatic solid masses in patients with or without chronic pancreatitis as well as the clinical parameters relevant to a malignancy when EUS-FNA was negative or inconclusive. METHODS: A total of 97 patients, who underwent EUS-FNA for solid pancreatic masses over 2 years at a single institution, were evaluated. All patients underwent EUS-FNA for 3-5 passes with 22 or 25 G needles without an on-site cytopathologist. The final diagnosis was obtained by surgery or compatible clinical outcomes for a more than 12 month follow-up. The diagnostic yields in the patients with or without chronic pancreatitis were compared and the histories and laboratory data relevant to pancreatic ductal adenocarcinoma (PDAC) or pseudo-tumor were analyzed. RESULTS: The final diagnoses were adenocarcinoma in 88 patients (90.7%) and inflammatory pseudo-tumor in 9 (9.3%). The results of EUS-FNA were adenocarcinoma (74), suspicious (7), atypical (5), negative (10), and inadequate specimen (1). The diagnostic accuracies were 76.9% and 91.6% in patients with or without chronic pancreatitis, respectively. Among the 23 cases with non-diagnostic results of EUS-FNA, PDAC was finally diagnosed in 5 out of 7 suspicious, 3 out of 5 atypical, and 5 out of 10 negative cytology cases. The clinical parameters related to a pseudo-tumor were a history of alcohol consumption and pancreatitis, and normal alkaline phosphatase levels. CONCLUSIONS: The diagnostic accuracy of pancreatic masses in the background of chronic pancreatitis was low. When EUS-FNA produced inconclusive results, the histories of alcohol consumption, pancreatitis, and serum levels of alkaline phosphatase are useful for making a final diagnosis.
Adenocarcinoma ; Alcohol Drinking ; Alkaline Phosphatase ; Biopsy, Fine-Needle* ; Diagnosis ; Endoscopic Ultrasound-Guided Fine Needle Aspiration ; Endosonography ; Follow-Up Studies ; Humans ; Needles ; Pancreatic Ducts ; Pancreatic Neoplasms ; Pancreatitis ; Pancreatitis, Chronic

PURPOSE: Study on the pathogen and the pathogen-related disease require the information at both cellular and organism level. However, lack of appropriate high-quality antibodies and the difference between the experimental animal models make it difficult to analyze in vivo mechanism of pathogen-related diseases. For more reliable research on the infection and immune-response of pathogen-related diseases, accurate analysis is essential to provide spatiotemporal information of pathogens and immune activity to avoid false-positive or mis-interpretations. In this regards, we have developed a method for tracking Francisella tularensis in the animal model without using the specific antibodies for the F. tularensis. MATERIALS AND METHODS: A dual reporter plasmid using GFP-Lux with putative bacterioferritin promoter (pBfr) was constructed and transformed to F. tularensis live vaccine strain to generate F. tularensis LVS (FtLVS)-GFP-Lux for both fluorescence and bioluminescence imaging. For vaccination to F. tularensis infection, FtLVS and lipopolysaccharide (LPS) from FtLVS were used. RESULTS: We visualized the bacterial replication of F. tularensis in the cells using fluorescence and bioluminescence imaging, and traced the spatio-temporal process of F. tularensis pathogenesis in mice. Vaccination with LPS purified from FtLVS greatly reduced the bacterial replication of FtLVS in animal model, and the effect of vaccination was also successfully monitored with in vivo imaging. CONCLUSION: We successfully established dual reporter labeled F. tularensis for cellular and whole body imaging. Our simple and integrated imaging analysis system would provide useful information for in vivo analysis of F. tularensis infection as well as in vitro experiments, which have not been fully explained yet with various technical problems.
Animals ; Antibodies ; Fluorescence ; Francisella tularensis* ; Francisella* ; Immunodeficiency Virus, Feline ; In Vitro Techniques ; Methods ; Mice ; Models, Animal ; Plasmids ; Vaccination ; Whole Body Imaging

Gliosarcoma (GS) is a rare variant (2%) of glioblastoma (GBM) that poses clinical genomic challenges because of its poor prognosis and limited genomic information. To gain a comprehensive view of the genomic alterations in GS and to understand the molecular etiology of GS, we applied whole-exome sequencing analyses for 28 GS cases (6 blood-matched fresh-frozen tissues for the discovery set, 22 formalin-fixed paraffin-embedded tissues for the validation set) and copy-number variation microarrays for 5 blood-matched fresh-frozen tissues. TP53 mutations were more prevalent in the GS cases (20/28, 70%) compared to the GBM cases (29/90, 32%), and the GS patients with TP53 mutations showed a significantly shorter survival (multivariate Cox analysis, hazard ratio=23.9, 95% confidence interval, 2.87–199.63, P=0.003). A pathway analysis showed recurrent alterations in MAPK signaling (EGFR, RASGRF2 and TP53), phosphatidylinositol/calcium signaling (CACNA1s, PLCs and ITPRs) and focal adhesion/tight junction (PTEN and PAK3) pathways. Genomic profiling of the matched recurrent GS cases detected the occurrence of TP53 mutations in two recurrent GS cases, which suggests that TP53 mutations play a role in treatment resistance. Functionally, we found that TP53 mutations are associated with the epithelial–mesenchymal transition (EMT) process of sarcomatous components of GS. We provide the first comprehensive genome-wide genetic alternation profiling of GS, which suggests novel prognostic subgroups in GS patients based on their TP53 mutation status and provides new insight in the pathogenesis and targeted treatment of GS.
Glioblastoma ; Gliosarcoma* ; Humans ; Prevalence* ; Prognosis

BACKGROUND: Forkhead box P3 (Foxp3) is the most reliable marker for regulatory T cells, which play an important role in maintaining renal allograft tolerance. Recently, Foxp3 polymorphisms have been reported to be associated with graft outcome in kidney transplantation. We analyzed the association of Foxp3 polymorphisms with renal allograft outcome. METHODS: Foxp3 polymorphisms (rs3761548 A/C, rs2280883 C/T, rs5902434 del/ATT, and rs2232365 A/G) were tested by PCR with sequence-specific primers (PCR-SSP) in 231 adult kidney transplantation recipients from 1996-2004 at Seoul National University Hospital. RESULTS: Patients with the rs3761548 CC genotype showed better graft survival than those with the AC or AA genotype (log rank test, P=0.03). Patients with the rs3761548 CC genotype also showed a lower rate of recurrence of the original glomerular disease than those with the AC or AA genotype (P=0.01). The frequency of acute rejection (AR) in patients with the rs2280883 TT genotype was lower than that in patients with the rs2280883 CT or CC genotype (26.9% vs 53.3%, P=0.038). Patients with the rs2280883 TT genotype also showed better graft survival than those with the CT or CC genotype (P=0.03). CONCLUSIONS: Foxp3 rs3761548 CC and rs2280883 TT genotypes were associated with superior graft outcome of kidney transplantation. Further studies involving a larger number of patients are needed.
Adult ; Allografts* ; Genotype ; Graft Survival ; Humans ; Kidney Transplantation* ; Kidney* ; Polymerase Chain Reaction ; Polymorphism, Single Nucleotide ; Recurrence ; Seoul ; T-Lymphocytes, Regulatory ; Transplantation Tolerance ; Transplants

Prostate-specific membrane antigen (PSMA) is an attractive target for both diagnosis and therapy because of its high expression in the vast majority of prostate cancers. Development of small molecules for targeting PSMA is important for molecular imaging and radionuclide therapy of prostate cancer. Recent evidence implies that androgendeprivation therapy increase PSMA-ligand uptake in some cases. The reported upregulations in PSMA-ligand uptake after exposure to second-generation antiandrogens such as enzalutamide and abiraterone might disturb PSMA-targeted imaging for staging and response monitoring of patients undergoing treatment with antiandrogen-based drugs. On the other hand, second-generation antiandrogens are emerging as potential endoradio-/chemosensitizers. Therefore, the enhancement of the therapeutic efficiency of PSMA-targeted theranostic methods can be listed as a new capability of antiandrogens. In this manuscript, we will present what is currently known about the mechanism of increasing PSMA uptake following exposure to antiandrogens. In addition, we will discuss whether these above-mentioned antiandrogens could play the role of endoradio-/chemosensitizers in combination with the well-established PSMA-targeted methods for pre-targeting of prostate cancer.
Androgen Antagonists ; Diagnosis ; Hand ; Humans ; Membranes ; Molecular Imaging ; Positron-Emission Tomography ; Prostatic Neoplasms ; Theranostic Nanomedicine

BACKGROUND: Angiogenesis is important for the proliferation and survival of multiple myeloma (MM) cells. Bone marrow (BM) microvessel density (MVD) is a useful marker of angiogenesis and is determined by immunohistochemical staining with anti-CD34 antibody. This study investigated the prognostic impact of MVD and demonstrated the relationship between MVD and previously mentioned prognostic factors in patients with MM. METHODS: The study included 107 patients with MM. MVD was assessed at initial diagnosis in a blinded manner by two hematopathologists who examined three CD34-positive hot spots per patient and counted the number of vessels in BM samples. Patients were divided into three groups according to MVD tertiles. Cumulative progression-free survival (PFS) and overall survival (OS) curves, calculated by using Kaplan-Meier method, were compared among the three groups. Prognostic impact of MVD was assessed by calculating Cox proportional hazard ratio (HR). RESULTS: Median MVDs in the three groups were 16.8, 33.9, and 54.7. MVDs were correlated with other prognostic factors, including beta2-microglobulin concentration, plasma cell percentage in the BM, and cancer stage according to the International Staging System. Multivariate Cox regression analysis showed that high MVD was an independent predictor of PFS (HR=2.57; 95% confidence interval, 1.22-5.42; P=0.013). PFS was significantly lower in the high MVD group than in the low MVD group (P=0.025). However, no difference was observed in the OS (P=0.428). CONCLUSIONS: Increased BM MVD is a marker of poor prognosis in patients newly diagnosed with MM. BM MVD should be assessed at the initial diagnosis of MM.
Aged ; Antigens, CD34/metabolism ; Bone Marrow/metabolism/*pathology ; Disease-Free Survival ; Female ; Humans ; Immunohistochemistry ; Kaplan-Meier Estimate ; Male ; Microvessels/*physiopathology ; Middle Aged ; Multiple Myeloma/*diagnosis/mortality ; Neoplasm Staging ; Neovascularization, Pathologic ; Plasma Cells/cytology ; Prognosis ; Proportional Hazards Models ; Regression Analysis ; Risk Factors

BACKGROUND: The impact of HLA and KIR ligand mismatching on the outcome of hematopoietic stem cell transplantation (HSCT) remains unclear. Previous reports have identified considerable ethnic differences in the impact of HLA and KIR ligand mismatches, as well as KIR ligand status, on HSCT; however, to date, no data has been acquired in Korean adult patients. METHODS: We investigated the association of high-resolution HLA matching on five loci (HLA-A, -B, -C, -DRB1, and -DQB1), KIR ligand mismatching, and KIR ligand status on the outcome of allogeneic HSCT from unrelated donors in 154 Korean adult patients treated at Seoul National University Hospital. RESULTS: In a multivariate analysis, less than 9/10 allelic matches in five HLA loci was an independent risk factor for acute graft-versus-host disease (GVHD) (grade II to IV) (P=0.019, odds ratio [OR]=2.7). In addition, HLA-A allele mismatching was increasingly prevalent in patients with acute GVHD compared to patients without (61.9% vs. 34.5%, P=0.06). For KIR ligand status, the patient and donor combination of both C1/C1 ligands showed better event-free and overall survival than combinations with C2 ligand patients or donors (P=0.048, P=0.034, respectively) by log-rank test. CONCLUSIONS: Korean adult transplant patients with less than 9 of 10 HLA allele matches in the HLA-A, -B, -C, -DRB1, and DQB1 loci have a higher likelihood of developing acute GVHD (grade II to IV). Impact of KIR ligand status on clinical outcome should be further studied in a larger patient population.
Adolescent ; Adult ; Alleles ; Female ; Genetic Loci ; Graft vs Host Disease/etiology ; HLA Antigens/*genetics/metabolism ; *Hematopoietic Stem Cell Transplantation/adverse effects/standards ; Histocompatibility Testing ; Humans ; Kaplan-Meier Estimate ; Leukemia/mortality/therapy ; Male ; Middle Aged ; Multivariate Analysis ; Receptors, KIR/*chemistry/metabolism ; Republic of Korea ; Risk Factors ; Transplantation, Homologous ; Young Adult