Split genome-based retroviral replicating vectors achieve efficient gene delivery and therapeutic effect in a human glioblastoma xenograft model.

The murine leukemia virus-based semi-retroviral replicating vectors (MuLV-based sRRV) had been developed to improve safety and transgene capacity for cancer gene therapy. However, despite the apparent advantages of the sRRV, improvements in the in vivo transduction efficiency are still required to deliver therapeutic genes efficiently for clinical use. In this study, we established a gibbon ape leukemia virus (GaLV) envelopepseudotyped semi-replication-competent retrovirus vector system (spRRV) which is composed of two transcomplementing replication-defective retroviral vectors termed MuLV-Gag-Pol and GaLV-Env. We found that the spRRV shows considerable improvement in efficiencies of gene transfer and spreading in both human glioblastoma cells and pre-established human glioblastoma mouse model compared with an sRRV system. When treated with ganciclovir after intratumoral injection of each vector system into pre-established U-87 MG glioblastomas, the group of mice injected with spRRV expressing the herpes simplex virus type 1-thymidine kinase (HSV1-tk) gene showed a survival rate of 100% for more than 150 days, but all control groups of mice (HSV1-tk/PBS-treated and GFP/GCV-treated groups) died within 45 days after tumor injection. In conclusion, these findings sug-gest that intratumoral delivery of the HSV1-tk gene by the spRRV system is worthy of development in clinical trials for the treatment of malignant solid tumors. [BMB Reports 2022; 55(12): 615-620].

Routine Functional Testing or Standard Care in High-Risk Patients after PCI.

BACKGROUND: There are limited data from randomized trials to guide a specific follow-up surveillance approach after myocardial revascularization. Whether a follow-up strategy that includes routine functional testing improves clinical outcomes among high-risk patients who have undergone percutaneous coronary intervention (PCI) is uncertain. METHODS: We randomly assigned 1706 patients with high-risk anatomical or clinical characteristics who had undergone PCI to a follow-up strategy of routine functional testing (nuclear stress testing, exercise electrocardiography, or stress echocardiography) at 1 year after PCI or to standard care alone. The primary outcome was a composite of death from any cause, myocardial infarction, or hospitalization for unstable angina at 2 years. Key secondary outcomes included invasive coronary angiography and repeat revascularization. RESULTS: The mean age of the patients was 64.7 years, 21.0% had left main disease, 43.5% had bifurcation disease, 69.8% had multivessel disease, 70.1% had diffuse long lesions, 38.7% had diabetes, and 96.4% had been treated with drug-eluting stents. At 2 years, a primary-outcome event had occurred in 46 of 849 patients (Kaplan-Meier estimate, 5.5%) in the functional-testing group and in 51 of 857 (Kaplan-Meier estimate, 6.0%) in the standard-care group (hazard ratio, 0.90; 95% confidence interval [CI], 0.61 to 1.35; P = 0.62). There were no between-group differences with respect to the components of the primary outcome. At 2 years, 12.3% of the patients in the functional-testing group and 9.3% in the standard-care group had undergone invasive coronary angiography (difference, 2.99 percentage points; 95% CI, -0.01 to 5.99), and 8.1% and 5.8% of patients, respectively, had undergone repeat revascularization (difference, 2.23 percentage points; 95% CI, -0.22 to 4.68). CONCLUSIONS: Among high-risk patients who had undergone PCI, a follow-up strategy of routine functional testing, as compared with standard care alone, did not improve clinical outcomes at 2 years. (Funded by the CardioVascular Research Foundation and Daewoong Pharmaceutical; POST-PCI ClinicalTrials.gov number, NCT03217877.).

Adult Presentation of Subaortic Stenosis with Subaortic Membrane Treated with Surgical Removal.

Subaortic stenosis (SAS) is a rare heart disease in adults with an unclear etiology and variable clinical presentation. In some cases, SAS appears as hypertrophic cardiomyopathy with obstruction due to the accompanying systolic anterior motion of the mitral valve. A 46-year-old male with dizziness for several months presented in the outpatient department. Two-dimensional transthoracic echocardiography demonstrated a slightly hypertrophic left ventricle with normal systolic function without wall-motion abnormalities. Just below the aortic valve, a linear structure protruding from the septum side and the left-ventricular outflow tract (LVOT) side of the mitral valve was confirmed, which was causing a significant pressure gradient (mean and maximum of 91 mmHg and 138 mmHg, respectively). A diagnosis of SAS with subaortic membrane was made, and surgical myomectomy and subaortic membrane removal surgery were performed. Postoperative transthoracic echocardiography did not show flow acceleration through the LVOT, nor a significant pressure gradient across the aortic valve. This case report highlights the clinical significance of SAS with subaortic membrane, which can be confused with aortic stenosis of other etiology.

11C-acetate and 18F-fluorodeoxyglucose positron emission tomography/computed tomography dual imaging for the prediction of response and prognosis after transarterial chemoembolization.

The aim of the present study was to evaluate the clinical significance of dual radiotracer studies, C-acetate and F-fluoro-D-glucose positron emission tomography/computed tomography (F-FDG PET/CT), for the prediction of response and recurrence after transarterial chemoembolization (TACE).This study retrospectively included a total 42 hepatoceullar carcinoma (HCC) patients (median age, 59; range, 34-85 years old) who underwent C-acetate and F-FDG PET/CT concurrently. Tumor uptake normalized by liver uptake (TNR; maximum tumor SUV to mean normal liver SUV ratio) was obtained first. Then, FAratio, which is the ratio of F-FDG TNR (TNR_FDG) to C-acetate TNR, was obtained and correlated with response after TACE and recurrence-free survival (RFS), using a Cox multivariate proportional-hazard model.Among clinical factors, including the Hepatoma Arterial Embolization Prognostic score and positron emission tomography (PET) parameters, multiple regression analysis revealed FAratio and tumor size to be the only significant factors. As a PET parameter, FAratio exhibited the largest area under the curve in the prediction of response after TACE. In the Cox multivariate proportional-hazard model, TNR_FDG was the only significant predictive factor for RFS. In subgroup analysis, TNR_FDG was the only significant predictive factor for recurrence in intermediate stage patients. However, FAratio was the only significant predictive factor for recurrence in advanced stage patients.Dual radiotracer use of C-acetate and F-FDG PET/CT contributed to the prediction of response and recurrence after TACE. Used in addition to F-FDG, C-acetate PET/CT could give additional information in advanced stage patients. Based on the characteristics of tumor metabolism assessed by dual radiotracer PET/CT, treatment plans could be more personalized and optimized.

Toward redesigning the PEG surface of nanocarriers for tumor targeting: impact of inner functionalities on size, charge, multivalent binding, and biodistribution.

Achieving accurate and efficacious tumor targeting with minimal off-target effects is of paramount importance in designing diagnostic and therapeutic agents for cancer. In this respect, nanocarriers have gained enormous popularity because of their attainable multifunctional features, as well as tumor-targeting potential by extravasation. However, once administered into the bloodstream, nanocarriers face various in vivo obstacles that may significantly impair their performance needed for clinical translation. Herein, we demonstrate a strategy to enhance tumor-targeting efficiency by embedding functionalities in the interior region of partially PEGylated nanocarriers (ca. 10 nm in diameter), intended for active or passive targeting. The cooperative impact of these topologically inner functional groups (IFGs) was marked: enhancements of >100-fold in IC50in vitro (e.g., a high-avidity ligand with cationic IFGs) and >2-fold in tumor accumulation at 2 h post-injection in vivo (e.g., a high-avidity ligand with anionic IFGs), both against the fully PEGylated counterpart. Analogous to allosteric modulators, properly employed IFGs may substantially improve the process of effectively directing nanocarriers to tumors, which is otherwise solely dependent on avidity or extravasation.

Generalizability of EXCEL and NOBLE results to a large registry population with unprotected left main coronary artery disease.

OBJECTIVE: The aim of this study was to determine how trial-based findings of EXCEL and NOBLE might be interpreted and generalizable in 'real-world' settings with comparison of data from the large-scaled, all-comer Interventional Research Incorporation Society-Left MAIN Revascularization (IRIS-MAIN) registry. PATIENTS AND METHODS: We compared baseline clinical and procedural characteristics and also determined how the relative treatment effect of percutaneous coronary intervention (PCI) and coronary artery bypass grafting (CABG) was different in EXCEL and NOBLE, compared with those of the multicenter, IRIS-MAIN registry (n=2481). The primary outcome for between-study comparison was a composite of death, myocardial infarction (MI), or stroke. RESULTS: There were between-study differences in patient risk profiles (age, BMI, diabetes, and clinical presentation), lesion complexities, and procedural characteristics (stent type, the use of off-pump surgery, and radial artery); the proportion of diabetes and acute coronary syndrome was particularly lower in NOBLE than in other studies. Although there was interstudy heterogeneity for the protocol definition of MI, the risks for serious composite outcome of death, MI, or stroke were similar between PCI and CABG in EXCEL [hazard ratio (HR): 1.00; 95% confidence interval (CI): 0.79-1.26; P=0.98] and in the matched cohort of IRIS-MAIN (HR: 1.08; 95%CI: 0.85-1.38; P=0.53), whereas it was significantly higher after PCI than after CABG in NOBLE (HR: 1.47; 95%CI: 1.06-2.05; P=0.02), which was driven by more common MI and stroke after PCI. CONCLUSION: In the comparison of a large-sized, all-comer registry, the EXCEL trial might represent better generalizability with respect to baseline characteristics and observed clinical outcomes compared with the NOBLE trial.

Differential Event Rates and Independent Predictors of Long-Term Major Cardiovascular Events and Death in 5795 Patients With Unprotected Left Main Coronary Artery Disease Treated With Stents, Bypass Surgery, or Medication: Insights From a Large International Multicenter Registry.

BACKGROUND: Identifying predictive factors for major cardiovascular events and death in patients with unprotected left main coronary artery disease is of great clinical value for risk stratification and possible guidance for tailored preventive strategies. METHODS AND RESULTS: The Interventional Research Incorporation Society-Left MAIN Revascularization registry included 5795 patients with unprotected left main coronary artery disease (percutaneous coronary intervention, n=2850; coronary-artery bypass grafting, n=2337; medication alone, n=608). We analyzed the incidence and independent predictors of major adverse cardiac and cerebrovascular events (MACCE; a composite of death, MI, stroke, or repeat revascularization) and all-cause mortality in each treatment stratum. During follow-up (median, 4.3 years), the rates of MACCE and death were substantially higher in the medical group than in the percutaneous coronary intervention and coronary-artery bypass grafting groups (P<0.001). In the percutaneous coronary intervention group, the 3 strongest predictors for MACCE were chronic renal failure, old age (≥65 years), and previous heart failure; those for all-cause mortality were chronic renal failure, old age, and low ejection fraction. In the coronary-artery bypass grafting group, old age, chronic renal failure, and low ejection fraction were the 3 strongest predictors of MACCE and death. In the medication group, old age, low ejection fraction, and diabetes mellitus were the 3 strongest predictors of MACCE and death. CONCLUSIONS: Among patients with unprotected left main coronary artery disease, the key clinical predictors for MACCE and death were generally similar regardless of index treatment. This study provides effect estimates for clinically relevant predictors of long-term clinical outcomes in real-world left main coronary artery patients, providing possible guidance for tailored preventive strategies. CLINICAL TRIAL REGISTRATION: URL: https://clinicaltrials.gov. Unique identifier: NCT01341327.

Comparative determinants of 5-year cardiovascular event rates in patients with unprotected left main coronary artery disease.

BACKGROUND: Diabetes mellitus (DM), low ejection fraction (EF), and the extent of coronary artery disease (CAD) have all been identified as predictors of cardiovascular events in multivessel disease, but their comparative contributions to future risk remain unclear in patients with unprotected left main coronary artery (ULMCA) disease. Through this study we aimed to categorize the risk for cardiovascular events in patients with ULMCA disease using simple clinical descriptors. PATIENTS AND METHODS: Our study included a total of 5975 patients with ULMCA disease from the Interventional Research Incorporation Society-Left MAIN Revascularization registry who were treated with percutaneous coronary intervention (n=2850), coronary artery bypass grafting (n=2337), or medical therapy alone (n=608). We categorized the risk for cardiovascular events using simple clinical descriptors (DM, low EF, and the extent of CAD). The primary outcome was a major adverse cardiac or cerebrovascular event (MACCE) (i.e. death from any cause, stroke, myocardial infarction, or repeat revascularization). RESULTS: Overall, the 5-year rate of MACCE was highest in the medical group, lower in the percutaneous coronary intervention group, and lowest in the coronary artery bypass grafting group (42.5, 25.7, and 19.9%, respectively; P<0.001). In multivariable modeling, the presence of DM [hazard ratio (HR): 1.25; 95% confidence interval (CI): 1.12-1.40; P<0.001], low EF of 40% or less (HR: 1.83; 95% CI: 1.56-2.15; P<0.001), and the extent of CAD (HR: 1.14; 95% CI: 1.08-1.21; P<0.001) were independent predictors of MACCE; in addition, these factors were consistently associated with a significantly higher risk for MACCE, regardless of index treatment strategies. CONCLUSION: Simple clinical descriptors can assist clinicians in identifying high-risk patients and in predicting future cardiovascular events within the broad range of risk factors for ULMCA disease.

Coronary Artery Bypass Grafting vs. Drug-Eluting Stent Implantation for Multivessel Disease in Patients with Chronic Kidney Disease.

BACKGROUND AND OBJECTIVES: There is currently a limited amount of data that demonstrate the optimal revascularization strategy for chronic kidney disease (CKD) patients with multivessel coronary artery disease (CAD). We compared the long-term outcomes of percutaneous coronary intervention (PCI) with drug-eluting stents (DES) versus coronary artery bypass graft surgery (CABG) for multivessel CAD in patients with CKD. SUBJECTS AND METHODS: We analyzed 2108 CKD patients (estimated glomerular filtration rate <60 mL/min/1.73 m2) with multivessel CAD that were treated with PCI with DES (n=1165) or CABG (n=943). The primary outcome was a composite of all causes of mortality, myocardial infarction, or stroke. The mean age was 66.9±9.1 years. RESULTS: Median follow-up duration was 41.4 (interquartile range 12.1-75.5) months. The primary outcome occurred in 307 (26.4%) patients in the PCI group compared with 304 (32.2%) patients in the CABG group (adjusted hazard ratio [HR], 0.941; 95% confidence interval [CI], 0.79-1.12; p=0.493). The two groups exhibited similar rates of all-cause mortality (adjusted HR, 0.91; 95% CI, 0.77-1.09; p=0.295), myocardial infarction (adjusted HR, 1.86; 95% CI, 0.85-4.07; p=0.120) and stroke (3.2% vs. 4.8%; HR, 0.93; 95% CI, 0.57-1.61; p=0.758). However, PCI was associated with significantly increased rates of repeat revascularization (adjusted HR, 4.72; 95% CI, 3.20-6.96; p<0.001). CONCLUSION: Among patients with CKD and multivessel CAD, PCI with DES when compared with CABG resulted in similar rates of composite outcome of mortality from any cause, MI, or stroke; however, a higher risk of repeat revascularization was observed.

Comparison of Outcomes of Coronary Artery Bypass Grafting Versus Drug-Eluting Stent Implantation in Patients With Severe Left Ventricular Dysfunction.

The optimal revascularization strategy for patients with significant coronary artery disease (CAD) and severe left ventricular (LV) dysfunction (ejection fraction ≤35%) remains unclear. We compared the effects of coronary artery bypass surgery (CABG, n = 442) versus percutaneous coronary intervention (PCI) with drug-eluting stents (n = 469) on long-term mortality in 911 patients with significant CAD and severe LV dysfunction using large real-world registry data. Databases of 3 real-world registries were merged for a patient-level meta-analysis. Primary outcome was death from any cause; secondary outcomes were death from cardiac causes, myocardial infarction, stroke, or repeat revascularization. At a median follow-up of 37.3 months, the risk of all-cause death (adjusted hazard ratio [HR] 0.43; 95% confidence interval [CI] 0.31 to 0.61; p <0.001) was significantly lower in the CABG group than in the PCI group after adjustment. Similar findings were observed with regard to the risks of death from cardiac cause (adjusted HR 0.49; 95% CI 0.33 to 0.73; p <0.001) and repeat revascularization (adjusted HR 0.08; 95% CI 0.03 to 0.20; p <0.001). However, there were no significant differences in the risks of myocardial infarction and stroke between the 2 groups. The superiority of CABG over PCI was particularly pronounced in patients receiving ß blockers and angiotensin-converting enzyme inhibitor or angiotensin receptor blockers than those who are not. In conclusion, among patients with significant CAD and severe LV dysfunction, CABG showed a lower risk of all-cause death, cardiac-cause death, and repeat revascularization compared with PCI with drug-eluting stents.

Fluorine-19 Magnetic Resonance Imaging and Positron Emission Tomography of Tumor-Associated Macrophages and Tumor Metabolism.

The presence of tumor-associated macrophages (TAMs) is significantly associated with poor prognosis of tumors. Currently, magnetic resonance imaging- (MRI-) based TAM imaging methods that use nanoparticles such as superparamagnetic iron oxide and perfluorocarbon nanoemulsions are available for quantitative monitoring of TAM burden in tumors. However, whether MRI-based measurements of TAMs can be used as prognostic markers has not been evaluated yet. In this study, we used positron emission tomography (PET) with 18F-2-fluoro-2-deoxy-D-glucose (18F-FDG) as a radioactive tracer and fluorine-19- (19F-) MRI for imaging mouse breast cancer models to determine any association between TAM infiltration and tumor metabolism. Perfluorocarbon nanoemulsions were intravenously administered to track and quantify TAM infiltration using a 7T MR scanner. To analyze glucose uptake in tumors, 18F-FDG-PET images were acquired immediately after 19F-MRI. Coregistered 18F-FDG-PET and 19F-MR images enabled comparison of spatial patterns of glucose uptake and TAM distribution in tumors. 19F-MR signal intensities from tumors exhibited a strong inverse correlation with 18F-FDG uptake while having a significant positive correlation with tumor growth from days 2 to 7. These results show that combination of 19F-MRI and 18F-FDG-PET can improve our understanding of the relationship between TAM and tumor microenvironment.

Successful Recanalization of Native Coronary Chronic Total Occlusion Is Not Associated With Improved Long-Term Survival.

OBJECTIVES: The purpose of this study was to evaluate long-term clinical outcomes after drug-eluting stent-supported percutaneous coronary intervention (PCI) for native coronary total occlusion (CTO). BACKGROUND: The benefit of successful recanalization of CTO on prognosis remains uncertain. METHODS: Between March 2003 and May 2014, 1,173 consecutive patients with CTO of native coronary vessels requiring PCI were enrolled. Drug-eluting stent implantation was performed in all successful procedures (1,004 patients, 85.6%). RESULTS: During a median follow-up of 4.6 years, the adjusted risks of all-cause mortality (hazard ratio [HR]: 1.04; 95% confidence interval [CI]: 0.53 to 2.04; p = 0.92) and the composite of death or myocardial infarction (HR: 1.05; 95% CI: 0.56 to 1.94; p = 0.89) were found to be comparable between patients with successful and failed CTO-PCI, whereas the adjusted risk of target vessel revascularization (HR: 0.15; 95% CI: 0.10 to 0.25; p < 0.001) and coronary artery bypass grafting (HR: 0.02; 95% CI: 0.006 to 0.06, p < 0.001) was significantly higher in patients with failed CTO-PCI. Among patients (n = 879) in whom complete revascularization for non-CTO vessels was performed, the risk of death or the composite of death or myocardial infarction were not found to differ between patients who underwent successful recanalization of the remaining CTO and patients who did not. This finding was consistent regardless of whether the patient had a multivessel disease including CTO or only had a single CTO disease. CONCLUSIONS: Successful CTO-PCI compared with failed PCI was not associated with a lesser risk for mortality. However, successful CTO-PCI was associated with significantly less subsequent coronary artery bypass grafting.

Image-aided Suicide Gene Therapy Utilizing Multifunctional hTERT-targeting Adenovirus for Clinical Translation in Hepatocellular Carcinoma.

Trans-splicing ribozyme enables to sense and reprogram target RNA into therapeutic transgene and thereby becomes a good sensing device for detection of cancer cells, judging from transgene expression. Previously we proposed PEPCK-Rz-HSVtk (PRT), hTERT targeting trans-splicing ribozyme (Rz) driven by liver-specific promoter phosphoenolpyruvate carboxykinase (PEPCK) with downstream suicide gene, herpes simplex virus thymidine kinase (HSVtk) for hepatocellular carcinoma (HCC) gene therapy. Here, we describe success of a re-engineered adenoviral vector harboring PRT in obtaining greater antitumor activity with less off-target effect for clinical application as a theranostics. We introduced liver-selective apolipoprotein E (ApoE) enhancer to the distal region of PRT unit to augment activity and liver selectivity of PEPCK promoter, and achieved better transduction into liver cancer cells by replacement of serotype 35 fiber knob on additional E4orf1-4 deletion of E1&E3-deleted serotype 5 back bone. We demonstrated that our refined adenovirus harboring PEPCK/ApoE-Rz-HSVtk (Ad-PRT-E) achieved great anti-tumor efficacy and improved ability to specifically target HCC without damaging normal hepatocytes. We also showed noninvasive imaging modalities were successfully employed to monitor both how well a therapeutic gene (HSVtk) was expressed inside tumor and how effectively a gene therapy took an action in terms of tumor growth. Collectively, this study suggests that the advanced therapeutic adenoviruses Ad-PRT-E and its image-aided evaluation system may lead to the powerful strategy for successful clinical translation and the development of clinical protocols for HCC therapy.

Immunoglobulin Fc-fused, neuropilin-1-specific peptide shows efficient tumor tissue penetration and inhibits tumor growth via anti-angiogenesis.

Neuropilin-1 (NRP1) receptor, involved in vascular endothelial growth factor (VEGF)-mediated vascular permeability and tumor angiogenesis, is targeted by peptides that bind to its VEGF-binding site. However, these peptides also cross-react with the structurally related receptor, NRP2. Here, we describe an immunoglobulin Fc-fused peptide, Fc-TPP11, which specifically binds to the VEGF-binding site of NRP1 with approximately 2nM affinity, but negligibly to that of NRP2. Fc-TPP11 triggered NRP1-dependent signaling, enhanced vascular permeability via vascular endothelial (VE)-cadherin downregulation, and increased paracellular permeability via E-cadherin downregulation in tumor tissues. Fc-TPP11 also significantly enhanced the tumor penetration of co-injected anti-cancer drug, doxorubicin, leading to the improved in vivo anti-tumor efficacy. Fc-TPP11 was easily adapted to the full-length anti-epidermal growth factor receptor (EGFR) monoclonal antibody (mAb) cetuximab (Erbitux), cetuximab-TPP11, exhibiting more than 2-fold improved tumor penetration than the parent cetuximab. Fc-TPP11 exhibited a similar whole-body half-life to that of intact Fc in tumor bearing mice. In addition to the tumor-penetrating activity, Fc-TPP11 suppressed VEGF-dependent angiogenesis by blocking VEGF binding to NRP1, thereby inhibiting tumor growth without promoting metastasis in the mouse model. Our results show that NRP1-specific, high-affinity binding of Fc-TPP11, is useful to validate NRP1 signaling, independent of NRP2. Thus, Fc-TPP11 can be used as a tumor penetration-promoting agent with anti-angiogenic activity or directly adapted to mAb-TPP11 format for more potent anti-cancer antibody therapy.

Comparison of sentinel lymph node biopsy guided by the multimodal method of indocyanine green fluorescence, radioisotope, and blue dye versus the radioisotope method in breast cancer: a randomized controlled trial.

PURPOSE: This study aimed to evaluate the identification rate and surgery time of sentinel lymph node biopsy (SLNB) by a multimodal method (MMM) using a mixture of indocyanine green (ICG), radioisotope (RI), and blue dye (BD) compared with the RI alone. METHODS: In this phase II randomized study, 86 patients with clinically node-negative breast cancer were enrolled and received SLNB with either MMM or RI. We compared the identification rate, number of sentinel lymph nodes (SLNs), and detection time of SLNB and evaluated the safety. RESULTS: The mean age of the MMM group and RI group was 48.2 and 51.0 years (p = 0.12), respectively. There were no differences in histopathologic factors, including tumor size, node positivity, and hormone receptor positivity between groups. SLNs were identified in all patients of both groups (100 % in the MMM group and 100 % in the RI group). The average number of SLNs in the MMM group was more than that in the RI group (3.4 ± 1.37 vs. 2.3 ± 1.04, respectively; p < 0.001). The time to detect the first sentinel lymph node was similar in each group (6.5 ± 5.16 vs. 8.0 ± 4.35 min; p = 0.13). In the MMM group, percutaneous lymphatic drainage was visualized by fluorescent imaging in 90.7 % (39 of 43 patients). During and after the operation, there were no complications, including allergic reactions, skin staining, or necrosis. CONCLUSIONS: This study is the first randomized trial that compared MMM using ICG, RI, and BD and the conventional RI method for SLNB. MMM is a feasible and safe method for SLNB.

Early determination of prognosis by interim 3'-deoxy-3'-18F-fluorothymidine PET in patients with non-Hodgkin lymphoma.

UNLABELLED: PET is a potentially useful modality for response analysis and prognosis prediction in patients with high-grade non-Hodgkin lymphoma (NHL). The thymidine analog 3'-deoxy-3'-(18)F-fluorothymidine ((18)F-FLT) was recently introduced as a new tracer. (18)F-FLT uptake correlates with tumor cell proliferation and is suggested to reflect early response to treatment. We performed a prospective study to evaluate the prognostic value of early interim (18)F-FLT PET in patients with NHL. METHODS: Patients with untreated NHL were enrolled between 2005 and 2007. Among them, 61 pairs of (18)F-FLT PET images were obtained at baseline (pre), after 1 cycle of chemotherapy (interim), and at the end of all scheduled first-line chemotherapy (final). All (18)F-FLT PET scans were interpreted by quantitative methods (maximum standardized uptake value [SUV max] and mean standardized uptake value [SUV mean]). Receiver-operating-characteristic curve analysis was performed to define (18)F-FLT PET positivity using a cutoff value predicting disease progression, relapse, or death. Survival outcome was measured by progression-free survival (PFS) and overall survival (OS) rates. RESULTS: Receiver-operating-characteristic curve analysis of SUV max for prediction of disease progression and death showed the highest area under the curve (AUC) in interim (18)F-FLT PET scans (AUC of 0.841 for PFS and 0.834 for OS, with a cutoff of 1.86; P < 0.001), compared with pre and final (18)F-FLT PET scans. The SUV mean in interim (18)F-FLT PET scans also showed better prediction (AUC of 0.842 for PFS and 0.824 for OS, with a cutoff value of 1.65; P < 0.001) than pre and final (18)F-FLT PET scans. Patients with an interim (18)F-FLT PET SUV max more than 1.86, who were defined as the interim PET-positive group, were associated with worse 5-y PFS and OS rates than the interim PET-negative group (for PFS: 52.0% vs. 80.7%, respectively, and P < 0.001; for OS: 56.2% vs. 81.4%, respectively, and P < 0.001). By multivariable analysis, the prognostic value of interim (18)F-FLT PET positivity by SUV max remained significant after adjustment with other prognostic factors (for PFS: hazard ratio, 7.82, 95% confidence interval, 1.65-36.96, and P = 0.009; for OS: hazard ratio, 5.55, 95% confidence interval, 1.47-33.77, and P = 0.014). CONCLUSION: In patients with aggressive NHL, early interim (18)F-FLT PET is a significant predictor of PFS and OS. Early (18)F-FLT PET imaging also has a potential to identify patients with delayed response and nonfavorable prognosis despite achieving a clinical complete response.

Bispecific Her2 × cotinine antibody in combination with cotinine-(histidine)2-iodine for the pre-targeting of Her2-positive breast cancer xenografts.

PURPOSE: Cotinine has optimal characteristics as a hapten for pre-targeted radioimmunotherapy (PRIT). This study was performed to evaluate the applicability of cotinine/anti-cotinine antibody to PRIT. METHODS: We developed and prepared a tandem, single-chain, variable fragment Fc fusion protein [tandem single-chain variable fragment (scFv) Fc fusion protein] that is reactive to both human epidermal growth factor receptor 2 (Her2) and cotinine. Its simultaneous reactivity to Her2 and cotinine was tested in an enzyme-linked immunosorbent assay (ELISA) and two radioimmunoassays (RIA) employing Her2-coated RIA tubes and a Her2-overexpressing cell line. For in vivo imaging, mice bearing Her2-positive tumors were injected with a mixture of tandem scFv Fc fusion and (125)I-cotinine-conjugated histidine dipeptide ((125)I-cotinine peptide). After a delay, (125)I-cotinine peptide was injected again. RESULTS: ELISA and RIA results showed that tandem scFv Fc fusion protein successfully bound to both Her2 and cotinine. In single-photon emission computed tomography (SPECT), the complex of tandem scFv Fc fusion protein and (125)I-cotinine peptide was localized to Her2-positive tumor xenografts in mice 4 h after the first injection. Enhanced radioactivity at the site of the Her2-positive tumor lesion was monitored 1 h after the second injection. CONCLUSIONS: With these findings, we conclude that the tandem scFv Fc fusion protein and cotinine hapten system have the potential to be applied in PRIT.

Prognostic predictors in pericardiectomy for chronic constrictive pericarditis.

OBJECTIVE: Prognosis after pericardiectomy remains to be clearly elucidated, especially in Asian countries, where the causes of constrictive pericarditis differ from those in Western countries. We aimed to investigate the preoperative prognostic factors and clinical outcomes after pericardiectomy in patients with chronic constrictive pericarditis. METHODS: Preoperative clinical and imaging characteristics were evaluated in 85 consecutive patients with chronic constrictive pericarditis without other valvular or ischemic heart diseases who underwent pericardiectomy. Causes were idiopathic in 49 patients (57.6%) and tuberculous in 36 patients (42.4%). All-cause death was observed for a median of 38.5 months. RESULTS: Of 85 patients, 15 (17.6%) died during follow-up. These 15 patients who died during follow-up had higher aspartate aminotransferase, smaller left ventricular end-systolic dimension index, and higher early diastolic mitral inflow velocity before pericardiectomy than the 70 patients who survived. Multivariate Cox proportional analysis showed that diabetes mellitus (hazard ratio, 4.610; P = .024) and high early diastolic mitral inflow velocity (hazard ratio, 1.050/cm/s; P = .002) before pericardiectomy were independent predictors of mortality after pericardiectomy. The preoperative cutoff value for early diastolic mitral inflow velocity in predicting mortality after pericardiectomy was 71 cm/s (sensitivity of 84.6% and specificity of 52.2%), and there was a significant difference in survival between groups divided by this cutoff value of early diastolic mitral inflow velocity (P = .029). CONCLUSIONS: Preoperative high early diastolic mitral inflow velocity and diabetes mellitus were predictors of poor prognosis after pericardiectomy in patients with chronic constrictive pericarditis. These results suggest that preoperative Doppler echocardiographic evaluation may be valuable not only for diagnosing constrictive pericarditis but also for predicting prognosis after pericardiectomy.