CdTe XG-Cam: A new high-resolution x-ray and gamma-ray camera for studies of the pharmacokinetics of radiopharmaceuticals in small animals.

BACKGROUND: The recent emergence of targeted radionuclide therapy has increased the demand for imagers capable of visualizing pharmacokinetics in developing radiopharmaceuticals in the preclinical phase. Some radionuclides emit hard x-rays and gamma-rays below 100 keV, in which energy range the performance of conventional NaI scintillators is poor. Multipinhole collimators are also used for small animal imaging with a good spatial resolution but have a limited field of view (FOV). PURPOSE: In this study, a new imager with high sensitivity over a wide FOV in the low-energy band ( < $<$ 100 keV) was developed for the pharmacokinetic study. METHODS: We developed an x-ray and gamma-ray camera for high-resolution spectroscopy, named "CdTe XG-Cam," equipped with a cadmium telluride semiconductor detector and a parallel-hole collimator using a metal 3D printer. To evaluate the camera-system performance, phantom measurements with single and dual nuclides ( 99 m Tc $^{\rm 99m}{\rm Tc}$ , 111 In $^{111}{\rm In}$ , and 125 I ) $^{125}{\rm I)}$ were performed. The performance for in vivo imaging was evaluated using tumor-bearing mice to which a nuclide ( 99 m Tc $^{\rm 99m}{\rm Tc}$ or 125 I ) $^{125}{\rm I)}$  administered. RESULTS: We simultaneously obtained information on 111 In $^{111}{\rm In}$ and 125 I $^{125}{\rm I}$ , which emit emission lines in the low-energy band with peak energies close to each other (23-26 keV for 111 In $^{111}{\rm In}$ and 27-31 keV for 125 I ) $^{125}{\rm I)}$ , and applied an analytical method based on spectral model fitting to determine the individual radioactivities accurately. In the small animal imaging, the distributions of the nuclide in tumors were accurately quantified and time-activity curves in tumors are obtained. CONCLUSIONS: The demonstrated capability of our system to perform in vivo imaging suggests that the camera can be used for applications of pharmacokinetics research.

Equivalent prognosis with no lymph node metastasis to pathological complete remission in patients with localized advanced esophageal cancer after neoadjuvant triplet chemotherapy with docetaxel, cisplatin, and 5-fluorouracil followed by curative surgery: a single-center retrospective cohort study.

Background: Adjuvant nivolumab therapy has become the standard therapy for patients with localized advanced esophageal cancer with non-pathological complete response after neoadjuvant chemoradiotherapy followed by curative surgery. However, the necessity of this therapy for patients after neoadjuvant chemotherapy (NAC) with docetaxel, cisplatin, and 5-fluorouracil (DCF) regimen followed by surgery is unclear, and the prognosis of grouping based on the presence or absence of pathological tumor and lymph node findings has not been analyzed. Therefore, our study aimed to address these questions. Methods: This retrospective cohort study included patients with cT1N1-3M0 and cT2-3N0-3M0 esophageal cancer according to the Japanese Classification of Esophageal Cancer, 11th edition, who received NAC with DCF followed by curative surgery between 2008 and 2020 at Jichi Medical University Hospital. We divided patients with ypT0-3N0-3M0 into four histological groups, namely ypT0N0, ypT+N0, ypT0N+, and ypT+N+, and we evaluated overall survival as the primary outcome and the prognostic relationship of lymph node metastasis as the secondary outcome. Results: A total of 101 patients were included in this study. Kaplan-Meier analysis showed that the curves of the ypT0N0 and ypT+N0 groups were almost identical, while they differed from the other two groups. The hazard ratio of ypN+ was 4.44 (95% confidence interval: 2.03-9.71; P<0.001). Conclusions: The prognosis of the ypT+N0 group after NAC with DCF followed by surgery was similar to that of pathological complete remission. Grouping patients according to pathological lymph node status is a reasonable predictor of prognosis.

Amelioration of Tumor-promoting Microenvironment via Vascular Remodeling and CAF Suppression Using E7130: Biomarker Analysis by Multimodal Imaging Modalities.

E7130 is a novel anticancer agent created from total synthetic study of the natural compound norhalichondrin B. In addition to inhibiting microtubule dynamics, E7130 also ameliorates tumor-promoting aspects of the tumor microenvironment (TME) by suppressing cancer-associated fibroblasts (CAF) and promoting remodeling of tumor vasculature. Here, we demonstrate TME amelioration by E7130 using multi-imaging modalities, including multiplexed mass cytometry [cytometry by time-of-flight (CyTOF)] analysis, multiplex IHC analysis, and MRI. Experimental solid tumors characterized by large numbers of CAFs in TME were treated with E7130. E7130 suppressed LAP-TGFß1 production, a precursor of TGFß1, in CAFs but not in cancer cells; an effect that was accompanied by a reduction of circulating TGFß1 in plasma. To our best knowledge, this is the first report to show a reduction of TGFß1 production in TME. Furthermore, multiplex IHC analysis revealed reduced cellularity and increased TUNEL-positive apoptotic cells in E7130-treated xenografts. Increased microvessel density (MVD) and collagen IV (Col IV), an extracellular matrix (ECM) component associated with endothelial cells, were also observed in the TME, and plasma Col IV levels were also increased by E7130 treatment. MRI revealed increased accumulation of a contrast agent in xenografts. Moreover, diffusion-weighted MRI after E7130 treatment indicated reduction of tumor cellularity and interstitial fluid pressure. Overall, our findings strongly support the mechanism of action that E7130 alters the TME in therapeutically beneficial ways. Importantly, from a translational perspective, our data demonstrated MRI as a noninvasive biomarker to detect TME amelioration by E7130, supported by consistent changes in plasma biomarkers.

A new simpler image quality index based on body size for FDG-PET/CT.

Noise equivalent count density (NEC density ) is often used to evaluate the image quality of whole-body fluorodeoxyglucose tomography tests. However, this index is calculated using the patient volume, which is difficult to obtain at every facility. In this study, we proposed new image quality indices that can be evaluated at all facilities. In total, 94 patients were enrolled in the study. The correlations of patients' body weight and BMI with volume were examined. New image quality indices normalized by body weight and BMI were defined as NEC bw and NEC bmi , respectively. Correlations between NEC bw , NEC bmi , and NEC density were examined. Further, the correlations between these two new indices and visual scores were evaluated. Good correlations were observed between volume and body weight (r = 0.861, P  < 0.001) and between volume and BMI (r = 0.728, P  < 0.001). NEC bw and NEC bmi correlated well with NEC density (r = 0.954 for NEC bw and r = 0.897 for NEC bmi , P  < 0.001). These correlations improved when the examined bed positions were set to the same number. Additionally, the correlations of visual scores with NEC bw and NEC bmi were similar to those between the visual score and NEC density . Our investigation indicated that the newly proposed image quality metrics, NEC bw and NEC bmi , were easily calculated and as useful as NEC density for evaluating image quality when subjects had similar physiques.

Dual-radionuclide in vivo imaging of micro-metastasis and lymph tract with submillimetre resolution.

Multi-radionuclide in vivo imaging with submillimetre resolution can be a potent tool for biomedical research. While high-resolution radionuclide imaging faces challenges in sensitivity, multi-radionuclide imaging encounters difficulty due to radiation contamination, stemming from crosstalk between radionuclides and Compton scattering. Addressing these challenges simultaneously is imperative for multi-radionuclide high-resolution imaging. To tackle this, we developed a high-spatial-resolution and high-energy-resolution small animal single-photon emission computed tomography (SPECT) scanner, named CdTe-DSD SPECT-I. We first assessed the feasibility of multi-tracer SPECT imaging of submillimetre targets. Using the CdTe-DSD SPECT-I, we performed SPECT imaging of submillimetre zeolite spheres absorbed with 125I- and subsequently imaged 125I-accumulated spheroids of 200-400 µm in size within an hour, achieving clear and quantitative images. Furthermore, dual-radionuclide phantom imaging revealed a distinct image of the submillimetre sphere absorbed with 125I- immersed in a 99mTc-pertechnetate solution, and provided a fair quantification of each radionuclide. Lastly, in vivo imaging was conducted on a cancer-bearing mouse with lymph node micro-metastasis using dual-tracers. The results displayed dual-tracer images of lymph tract by 99mTc-phytic acid and the submillimetre metastatic lesion by 125I-, shown to align with the immunofluorescence image.

3D-OSEM versus FORE + OSEM: Optimal Reconstruction Algorithm for FDG PET with a Short Acquisition Time.

Objective In this study, we investigated the optimal reconstruction algorithm in fluorodeoxyglucose (FDG) positron emission tomography (PET) with a short acquisition time. Materials and Methods In the phantom study, six spheres filled with FDG solution (sphere size: 6.23-37 mm; radioactivity ratio of spheres to background = 8:1) and placed in a National Electrical Manufacturers Association phantom were evaluated. Image acquisition time was 15 to 180 seconds, and the obtained image data were reconstructed using each of the Fourier rebinning (FORE) + ordered subsets expectation-maximization (OSEM) and 3D-OSEM algorithms. In the clinical study, mid-abdominal images of 19 patients were evaluated using regions of interest placed on areas of low, intermediate, and high radioactivity. All obtained images were investigated visually, and quantitatively using maximum standardized uptake value (SUV) and coefficient of variation (CV). Results In the phantom study, FORE + OSEM images with a short acquisition time had large CVs (poor image quality) but comparatively constant maximum SUVs. 3D-OSEM images showed comparatively constant CVs (good image quality) but significantly low maximum SUVs. The results of visual evaluation were well correlated with those of quantitative evaluation. Small spheres were obscured on 3D-OSEM images with short acquisition time, but image quality was not greatly deteriorated. The clinical and phantom studies yielded similar results. Conclusion FDG PET images with a short acquisition time reconstructed by FORE + OSEM showed poorer image quality than by 3D-OSEM. However, images obtained with a short acquisition time and reconstructed with FORE + OSEM showed clearer FDG uptake and more useful than 3D-OSEM in the light of the detection of lesions.

New liposome-radionuclide-chelate combination for tumor targeting and rapid healthy tissue clearance.

Radionuclide imaging and therapy are promising methods for controlling systemic cancers; however, their clinical application has been limited by excessive radionuclide accumulation in healthy tissues. To minimize radionuclide accumulation in non-cancerous tissues while ensuring sufficient build up in tumors, we aimed to develop a method that controlled the in vivo dynamics of radionuclides post-administration. To this end, we describe a novel strategy that combines liposomes, a potent carrier system for drug delivery, with unique radionuclide-ligand complexes based on 111In-ethylenedicysteine. Conventional 111In-ligand-complexes-carrying liposomes delivered substantial amounts of radionuclides to tumors; however, they also accumulated in the liver and spleen. In contrast, 111In-ethylenedicysteine-carrying liposomes greatly reduced non-specific accumulation, while being retained selectively at high doses within tumors. Liposomes were rapidly broken down in the liver, releasing encapsulated 111In-ligand complexes. Among the chelates used, only 111In-ethylenedicysteine could escape from the liver and be excreted in the urine. Instead, most liposomes remained intact in tumors, retaining the radionuclide-ligand complexes within them. Therefore, high tumor accumulation was obtained regardless of the type of 111In-ligand complexes in the liposomes. In vivo single photon emission computed tomography/computed tomography imaging with 111In-ethylenedicysteine-carrying liposomes accurately revealed tumor-selective radionuclide retention with little background. Hence, our new strategy could greatly enhance tumor-to-healthy tissue ratios, improve diagnostic imaging, boost therapeutic efficacy, reduce toxicity to healthy tissues, and facilitate radionuclide imaging and therapy.

Influence of Carboxyl Group Ratios on the Design of Breast Cancer Targeting Bimodal MR/NIR-II Imaging Probe from PLGA@Gd-DOTA@PEG Micelles Conjugating Herceptin.

We developed a small MRI/NIR-II probe to target HER2 (tetanucleotide) breast cancer cells. The probe is composed of PLGA-b-PEG micelles encapsulated NIR-II, and Gd-DOTA is conjugated at the border of PLGA/PEG. Herceptin was then conjugated to carboxyl residues of PLGA-b-PEG chains. We examined the influence of carboxyl group ratios on the probe property stability and Herceptin concentration and the binding affinity to HER2(+) cells corresponding to the -COOH ratios. The binding assays demonstrated that the optimal surface ratio of -COOH is 5%, which is less affected by fluorescence reduction and which exhibited the highest antigen-capturing activity.

Precise characterization of a corridor-shaped structure in Khufu's Pyramid by observation of cosmic-ray muons.

Khufu's Pyramid is one of the largest archaeological monument all over the world, which still holds many mysteries. In 2016 and 2017, the ScanPyramids team reported on several discoveries of previously unknown voids by cosmic-ray muon radiography that is a non-destructive technique ideal for the investigation of large-scale structures. Among these discoveries, a corridor-shaped structure has been observed behind the so-called Chevron zone on the North face, with a length of at least 5 meters. A dedicated study of this structure was thus necessary to better understand its function in relation with the enigmatic architectural role of this Chevron. Here we report on new measurements of excellent sensitivity obtained with nuclear emulsion films from Nagoya University and gaseous detectors from CEA, revealing a structure of about 9 m length with a transverse section of about 2.0 m by 2.0 m.

Tumor Targeting of 211At-Labeled Antibody under Sodium Ascorbate Protection against Radiolysis.

Astatine-211 (211At) is an alpha emitter applicable to radioimmunotherapy (RIT), a cancer treatment that utilizes radioactive antibodies to target tumors. In the preparation of 211At-labeled monoclonal antibodies (211At-mAbs), the possibility of radionuclide-induced antibody denaturation (radiolysis) is of concern. Our previous study showed that this 211At-induced radiochemical reaction disrupts the cellular binding activity of an astatinated mAb, resulting in attenuation of in vivo antitumor effects, whereas sodium ascorbate (SA), a free radical scavenger, prevents antibody denaturation, contributing to the maintenance of binding and antitumor activity. However, the influence of antibody denaturation on the pharmacokinetics of 211At-mAbs relating to tumor accumulation, blood circulation time, and distribution to normal organs remains unclear. In this study, we use a radioactive anti-human epidermal growth factor receptor 2 (anti-HER2) mAb to demonstrate that an 211At-induced radiochemical reaction disrupts active targeting via an antigen-antibody interaction, whereas SA helps to maintain targeting. In contrast, there was no difference in blood circulation time as well as distribution to normal organs between the stabilized and denatured immunoconjugates, indicating that antibody denaturation may not affect tumor accumulation via passive targeting based on the enhanced permeability and retention effect. In a high-HER2-expressing xenograft model treated with 1 MBq of 211At-anti-HER2 mAbs, SA-dependent maintenance of active targeting contributed to a significantly better response. In treatment with 0.5 or 0.2 MBq, the stabilized radioactive mAb significantly reduced tumor growth compared to the denatured immunoconjugate. Additionally, through a comparison between a stabilized 211At-anti-HER2 mAb and radioactive nontargeted control mAb, we demonstrate that active targeting significantly enhances tumor accumulation of radioactivity and in vivo antitumor effect. In RIT with 211At, active targeting contributes to efficient tumor accumulation of radioactivity, resulting in a potent antitumor effect. SA-dependent protection that successfully maintains tumor targeting will facilitate the clinical application of alpha-RIT.

High Resolution MR Imaging of the Testis Using a Small Radiofrequency Coil.

We have developed a new device, consisting of a 3-cm RF coil and an immobilizer, to acquire high-resolution MR images of the testis. With the approval of our institutional review board, we conducted an MRI study on a cohort of healthy volunteers to test this device. With the participants in the supine position, we placed the dedicated immobilizer and RF coil on the scrotum for typically no more than 3 min. Subsequently, T2-weighted images were acquired with an in-plane resolution of 117 µm using a 3-T MR scanner and the periodically rotated overlapping parallel lines with enhanced reconstruction (PROPELLER) sequence. The total scan time ranged from 12 to 30 min (average 20 min). High-resolution MR images of the testis were acquired without deterioration by motion artifacts. Our results showed that the combined use of a small RF coil and an immobilizer is a feasible option for acquiring high-resolution MR images of the testis.

The effect of Gd-DOTA locations within PLGA-b-PEG micelle encapsulated IR-1061 on bimodal over-1000 nm near-infrared fluorescence and magnetic resonance imaging.

Multimodal imaging is attractive in biomedical research because it can provide multidimensional information about objects that individual techniques cannot accomplish. In particular, combining over one-thousand-nanometer near-infrared (OTN-NIR) fluorescence and magnetic resonance (MR) imaging is promising for detecting lesions with high sensitivity and structural information. Herein, we describe the development of a bimodal OTN-NIR/MRI probe from gadolinium-tetraazacyclododecanetetraacetic acid (Gd-DOTA) conjugated poly(lactic-co-glycolic acid)-block-poly(ethylene glycol) copolymer (PLGA-b-PEG) micelle encapsulated IR-1061 at two different locations. One configuration contains Gd-DOTA at the end of the PEG of the hydrophilic shell and the other contains Gd-DOTA at the border of PLGA/PEG. The two structures show remarkable differences in fluorescence and R1 relaxation rates in biological environments; the structure with Gd-DOTA at the border of PLGA/PEG exhibits stable fluorescence and T1 signal distribution in live mice. The introduction ratio of Gd-DOTA to PEG is significant for controlling the properties of both structures; a higher Gd-DOTA ratio is preferable for the contrast enhancement effect. We found that Gd-DOTA ratios higher than 10% degraded the fluorescence intensity when Gd-DOTA was bound to the end of PEG. In contrast, the introduction of 70% Gd-DOTA at the border of PLGA/PEG did not exhibit a degraded signal, and the structural stability was enhanced with higher ratios of Gd-DOTA. In conclusion, we confirmed that the location of Gd-DOTA is a crucial factor in designing high-performance probes. The overall properties improve when Gd-DOTA is set on the border of PLGA/PEG. These improvements in the properties by controlling the probe structures are promising for future biomedical applications.

Real-world clinical outcomes in Japanese patients with locally advanced squamous cell carcinoma of the head and neck treated with radiotherapy plus cetuximab: a prospective observational study (JROSG12-2).

BACKGROUND: Radiotherapy plus cetuximab (bioradiotherapy: BRT) is a standard option in the treatment of locally advanced squamous cell carcinoma of the head and neck (LA-SCCHN). Published data on its safety and efficacy in real-world settings is limited. Here, we conducted a prospective multi-institutional observational study to evaluate clinical outcomes of BRT in patients with LA-SCCHN. METHODS: We analyzed real-world data of all patients who underwent BRT from 2013 to 2016. The primary endpoint was 1-year progression-free survival (PFS). Secondary endpoints were 1-year locoregional PFS (LPFS), treatment completion rate (TCR), and adverse events (AEs). RESULTS: A total of 171 patients with a minimum 1-year follow-up were analyzed. Median age was 67 (36-85) years, and 37 patients (21.6%) were aged 75 years or older. 1-year PFS and LPFS were 51.5 and 56.1%, respectively. N stage (p = 0.049) was significantly associated with PFS. TCR was 77.2%. Cetuximab was definitively discontinued in 30 patients (17.5%), in 15 cases due to severe mucositis. N stage, T stage, and comorbidity were significantly associated with TCR. Major AEs of grade 3 or higher were pharyngeal mucositis (48.5%), radiation dermatitis (45.6%), and oral mucositis (40.4%). Pneumonitis was observed in 12 patients (7.0%); 6 cases (3.5%) were grades 3-4 and 2 (1.2%) were grade 5. CONCLUSION: As a result of the large number of elderly patients in clinical practice,　toxicity reduced TCR. BRT-induced pneumonitis, which is sometimes fatal, was found to be more frequent than with chemotherapy plus cetuximab.

Protection from contamination by 211At, an enigmatic but promising alpha-particle-emitting radionuclide.

PURPOSE: 211At, a promising alpha-particle-emitting radionuclide, can easily volatilize and contaminate the environment. To safely manage this unique alpha-particle-emitting radionuclide, we investigated the permeability of four types of plastic films and two types of rubber gloves against 211At and identified suitable materials that prevent contamination by 211At. METHODS: Four types of plastic films, polyethylene, polyvinylidene chloride, polyvinyl chloride, and a laminated film, and two types of rubber gloves, latex and nitrile, were examined. Small pieces of filter paper were covered with these materials, and a drop containing 100 kBq of 211At was placed on them. The radioactivity of the pieces of filter paper under the materials was evaluated by measuring counts using a gamma counter and obtaining autoradiograms 3.5 h later. These experiments were also performed using 225Ac, 125I, 111In, 201Tl, and 99mTc. RESULTS: 211At solution easily penetrated polyethylene, polyvinyl chloride, and latex rubber. Similar results were obtained for 125I, while other radionuclides did not penetrate films or gloves. These results suggest that halogenic radionuclides under anionic conditions are likely to penetrate plastic films and rubber gloves. CONCLUSION: Our evaluation revealed that, when 211At solution is used, the protection by polyvinylidene chloride, a laminated film, or nitrile rubber would be more effective than that by polyethylene, polyvinyl chloride, or latex rubber.

New Cluster Analysis Method for Quantitative Dynamic Contrast-Enhanced MRI Assessing Tumor Heterogeneity Induced by a Tumor-Microenvironmental Ameliorator (E7130) Treatment to a Breast Cancer Mouse Model.

BACKGROUND: Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) can provide insight into tumor perfusion. However, a method that can quantitatively measure the intra-tumor distribution of tumor voxel clusters with a distinct range of Ktrans and ve values remains insufficiently explored. HYPOTHESIS: Two-dimensional cluster analysis may quantify the distribution of a tumor voxel subregion with a distinct range of Ktrans and ve values in human breast cancer xenografts. STUDY TYPE: Prospective longitudinal study. ANIMAL MODEL: Twenty-two female athymic nude mice with MCF-7 xenograft, treated with E7130, a tumor-microenvironmental ameliorator, or saline. FIELD STRENGTH/SEQUENCE: 9.4 Tesla, turbo rapid acquisition with relaxation enhancement, and spoiled gradient-echo sequences. ASSESSMENT: We performed two-dimensional k-means clustering to identify tumor voxel clusters with a distinct range of Ktrans and ve values on Days 0, 2, and 5 after treatment, calculated the ratio of the number of tumor voxels in each cluster to the total number of tumor voxels, and measured the normalized distances defined as the ratio of the distance between each tumor voxel and the nearest tumor margin to a tumor radius. STATISTICAL TESTS: Unpaired t-tests, Dunnett's multiple comparison tests, and Chi-squared test were used. RESULTS: The largest and second largest clusters constituted 44.4% and 27.5% of all tumor voxels with cluster centroid values of Ktrans at 0.040 min-1 and 0.116 min-1 , and ve at 0.131 and 0.201, respectively. At baseline (Day 0), the average normalized distances for the largest and second largest clusters were 0.33 and 0.24, respectively. E7130-treated group showed the normalized distance of the initial largest cluster decreasing to 0.25, while that of the second largest cluster increasing to 0.31. Saline-treated group showed no change. DATA CONCLUSION: A two-dimensional cluster analysis might quantify the spatial distribution of a tumor subregion with a distinct range of Ktrans and ve values. LEVEL OF EVIDENCE: 1 TECHNICAL EFFICACY: Stage 1.

Simultaneous visualization of multiple radionuclides in vivo.

The insufficient energy and spatial resolutions of radionuclide imaging with conventional scintillation detectors restrict the visualization of multiple radionuclides and of microstructures in tissue. Here we report the development and performance of an imaging system equipped with a cadmium telluride diode detector that achieves an energy resolution of 1.7% at 140 keV and a spatial resolution of 250 µm. The combination of high-resolution spectra fitted to an X-ray analysis model of the emission lines of the radionuclides in a chosen energy band allowed us to accurately determine individual radiation activities from three radionuclides to simultaneously visualize thyroid tissue (via intravenously administered iodine-125), mandibular lymph nodes (via the intramuscular injection of indium-111) and parotid lymph nodes (via a subcutaneous injection of technetium-99m) in mice. Multi-radionuclide imaging may find advantageous applications in biomedical imaging.

Weekly Cisplatin Plus Radiation for Postoperative Head and Neck Cancer (JCOG1008): A Multicenter, Noninferiority, Phase II/III Randomized Controlled Trial.

PURPOSE: The standard treatment for postoperative high-risk locally advanced squamous cell carcinoma of the head and neck (LA-SCCHN) is chemoradiotherapy with 3-weekly cisplatin (100 mg/m2). However, whether chemoradiotherapy with weekly cisplatin (40 mg/m2) yields comparable efficacy with 3-weekly cisplatin in postoperative high-risk LA-SCCHN is unknown. PATIENTS AND METHODS: In this multi-institutional open-label phase II/III trial, patients with postoperative high-risk LA-SCCHN were randomly assigned to receive either chemoradiotherapy with 3-weekly cisplatin (100 mg/m2) or with weekly cisplatin (40 mg/m2) to confirm the noninferiority of weekly cisplatin. The primary end point of phase II was the proportion of treatment completion, and that of phase III was overall survival. A noninferiority margin of hazard ratio was set at 1.32. RESULTS: Between October 2012 and December 2018, a total of 261 patients were enrolled (3-weekly cisplatin, 132 patients; weekly cisplatin, 129 patients). At the planned third interim analysis in the phase III part, after a median follow-up of 2.2 (interquartile range 1.19-3.56) years, chemoradiotherapy with weekly cisplatin was noninferior to 3-weekly cisplatin in terms of overall survival, with a hazard ratio of 0.69 (99.1% CI, 0.374 to 1.273 [< 1.32], one-sided P for noninferiority = .0027 < .0043). Grade 3 or more neutropenia and infection were less frequent in the weekly arm (3-weekly v weekly, 49% v 35% and 12% v 7%, respectively), as were renal impairment and hearing impairment. No treatment-related death was reported in the 3-weekly arm, and two (1.6%) in the weekly arm. CONCLUSION: Chemoradiotherapy with weekly cisplatin is noninferior to 3-weekly cisplatin for patients with postoperative high-risk LA-SCCHN. These findings suggest that chemoradiotherapy with weekly cisplatin can be a possible treatment option for these patients.

The influence of Gd-DOTA conjugating ratios to PLGA-PEG micelles encapsulated IR-1061 on bimodal over-1000 nm near-infrared fluorescence and magnetic resonance imaging.

Multimodal imaging can provide multidimensional information for understanding concealed microstructures or bioprocesses in biological objects. The combination of over-1000 nm near-infrared (OTN-NIR) fluorescence imaging and magnetic resonance (MR) imaging is promising in providing high sensitivity and structural information of lesions. This combination can be facilitated by the development of an imaging probe. The OTN-NIR and MR bimodal fluorescence probes reported to date primarily involve ceramic particles for fluorescence and MRI contrast enhancement effect. In this study, we designed a new bimodal OTN-NIR/MR imaging probe from organic components including an OTN-NIR fluorescent organic dye (IR-1061) encapsulated in the core of a micelle composed of poly(lactic-co-glycolic acid)-block-poly(ethylene glycol) copolymer (PLGA-PEG). For the MRI contrast, gadobutrol (Gd-DOTA) was introduced at the end of the PEG chain at various ratios. Thereafter, the OTN-NIR fluorescence and MR bimodal imaging probes of ca. 20 nm in size were successfully prepared and applied in mouse imaging. The probe exhibited absorption and emission in the OTN-NIR, and T1 contrast enhancement effects on MRI. Moreover, it demonstrated bright OTN-NIR fluorescence and MRI contrast enhancement to depict veins and observe the organs in live mice. The imaging results revealed that the Gd-DOTA introduction ratio is of great importance for controlling the biological response of the probe without reducing the contrast enhancement effect.

Evaluation of Aminopolycarboxylate Chelators for Whole-Body Clearance of Free 225Ac: A Feasibility Study to Reduce Unexpected Radiation Exposure during Targeted Alpha Therapy.

Actinium-225 (225Ac) is a promising radionuclide used in targeted alpha therapy (TAT). Although 225Ac labeling of bifunctional chelating ligands is effective, previous in vivo studies reported that free 225Ac can be released from the drugs and that such free 225Ac is predominantly accumulated in the liver and could cause unexpected toxicity. To accelerate the clinical development of 225Ac TAT with a variety of drugs, preparing methods to deal with any unexpected toxicity would be valuable. The aim of this study was to evaluate the feasibility of various chelators for reducing and excreting free 225Ac and compare their chemical structures. Nine candidate chelators (D-penicillamine, dimercaprol, Ca-DTPA, Ca-EDTA, CyDTA, GEDTA TTHA, Ca-TTHA, and DO3A) were evaluated in vitro and in vivo. The biodistribution and dosimetry of free 225Ac were examined in mice before an in vivo chelating study. The liver exhibited pronounced 225Ac uptake, with an estimated human absorbed dose of 4.76 SvRBE5/MBq. Aminopolycarboxylate chelators with five and six carboxylic groups, Ca-DTPA and Ca-TTHA, significantly reduced 225Ac retention in the liver (22% and 30%, respectively). Significant 225Ac reductions were observed in the heart and remainder of the body with both Ca-DTPA and Ca-TTHA, and in the lung, kidney, and spleen with Ca-TTHA. In vitro interaction analysis supported the in vivo reduction ability of Ca-DTPA and Ca-TTHA. In conclusion, aminopolycarboxylate chelators with five and six carboxylic groups, Ca-DTPA and Ca-TTHA, were effective for whole-body clearance of free 225Ac. This feasibility study provides useful information for reducing undesirable radiation exposure from free 225Ac.