High efficacy of particle beam therapies against tumors under hypoxia and prediction of the early stage treatment effect using 3'-deoxy-3'-[18F]fluorothymidine positron emission tomography.

OBJECTIVE: Compared with radiation therapy using photon beams, particle therapies, especially those using carbons, show a high relative biological effectiveness and low oxygen enhancement ratio. Using cells cultured under normoxic conditions, our group reported a greater suppressive effect on cell growth by carbon beams than X-rays, and the subsequent therapeutic effect can be predicted by the cell uptake amount of 3'-deoxy-3'-[18F]fluorothymidine (18F-FLT) the day after treatment. On the other hand, a hypoxic environment forms locally around solid tumors, influencing the therapeutic effect of radiotherapy. In this study, the influence of tumor hypoxia on particle therapies and the ability to predict the therapeutic effect using 18F-FLT were evaluated. METHODS: Using a murine colon carcinoma cell line (colon 26) cultured under hypoxic conditions (1.0% O2 and 5.0% CO2), the suppressive effect on cell growth by X-ray, proton, and carbon irradiation was evaluated. In addition, the correlation between decreased 18F-FLT uptake after irradiation and subsequent suppression of cell proliferation was investigated. RESULTS: Tumor cell growth was suppressed most efficiently by carbon-beam irradiation. 18F-FLT uptake temporarily increased the day after irradiation, especially in the low-dose irradiation groups, but then decreased from 50 h after irradiation, which is well correlated with the subsequent suppression on tumor cell growth. CONCLUSIONS: Carbon beam treatment shows a strong therapeutic effect against cells under hypoxia. Unlike normoxic tumors, it is desirable to perform 18F-FLT positron emission tomography 2-3 days after irradiation for early prediction of the treatment effect.

Effect of newly developed scissors-attached micro-forceps on the recipient clamp time and occurrence of anastomotic site infarction after bypass surgery for moyamoya disease.

Introduction: This study aimed to examine the effect of newly developed scissors-attached micro-forceps in superficial temporal artery-to-middle cerebral artery (STA-MCA) anastomosis for moyamoya disease (MMD). Materials and methods: Of 179 consecutive STA-MCA anastomoses on 95 hemispheres of 71 MMD patients at the University of Fukui Hospital between 2009 and 2023, 49 anastomoses on 26 hemispheres of 21 patients were enrolled in this retrospective cohort clinical trial intraoperative indocyanine green video-angiography did not demonstrate bypass patency in three anastomoses in two patients who were excluded. Twenty-one anastomosis in 19 hemispheres of 16 patients were performed using the conventional micro-forceps (conventional group, CG), and 25 anastomoses in 22 hemispheres of 19 patients were performed using scissors-attached micro-forceps (scissors group, SG). A small infarction near the anastomotic site detected using postoperative diffusion-weighted imaging was defined as anastomotic site infarction (ASI). Factors affecting the occurrence of ASI were examined by univariate, logistic regression, and receiver operating curve (ROC) analysis. Results: There were no significant differences in clinical parameters such as age, sex, number of sacrificed branches, number of sacrificed large branches, and number of sutures between the CG and SG. However, the clamp time and occurrence of ASI were significantly lower in the SG than in the CG. Logistic regression analysis revealed that the clamp time was the only significant factor predicting the occurrence of ASI. A receiver operating curve analysis also revealed that the clamp time significantly predicted the occurrence of ASI (area under the curve, 0.875; cutoff value, 33.2 min). Conclusion: The newly developed scissors-attached micro-forceps could significantly reduce the clamp time and occurrence of ASI in STA-MCA anastomosis for MMD.

Hematopoiesis in the spleen after engraftment in unrelated cord blood transplantation evaluated by 18F-FLT PET imaging.

Cord blood is an important donor source for allogeneic hematopoietic stem cell transplantation (allo-HSCT), with its unique composition and quality of hematopoietic cells. The proliferation site and potency of infused hematopoietic stem cells in humans may vary between stem cell sources. We investigated this possibility in a prospective, exploratory study to assess hematopoietic dynamics using the radiopharmaceutical 3'-deoxy-3'-18F-fluorothymidine (18F-FLT), a thymidine analog used in positron emission tomography imaging, before allo-HSCT and on days 50 and 180 after allo-HSCT. We evaluated 11 patients with hematological malignancies who underwent allo-HSCT [five with peripheral blood stem cell transplantation (PBSCT) and six with unrelated cord blood transplantation (UCBT)]. Before allo-HSCT, 18F-FLT uptake did not differ between the two groups. At day 50, 18F-FLT uptake in the spleen was significantly greater in the UCBT group than in the PBSCT group (p = 0.0043), with no difference in whole-body bone marrow. At day 180, the differences in spleen uptake had diminished, and there were no differences between groups in whole-body bone marrow or the spleen, except for the sternum. The persistence of splenic hematopoiesis after engraftment in the UCBT group may reflect the complex systemic homing and proliferation mechanisms of cord blood hematopoietic cells.

[18F]FES PET Resolves the Diagnostic Dilemma of COVID-19-Vaccine-Associated Hypermetabolic Lymphadenopathy in ER-Positive Breast Cancer.

Coronavirus disease (COVID-19) vaccination is known to cause a diagnostic dilemma due to false-positive findings on [18F]FDG PET in vaccine-associated hypermetabolic lymphadenopathy. We present two case reports of women with estrogen-receptor (ER)-positive cancer of the breast who were vaccinated for COVID-19 in the deltoid muscle. [18F]FDG positron emission tomography (PET) demonstrated primary breast cancer and multiple axillary lymph nodes with increased [18F]FDG uptake, diagnosed as vaccine-associated [18F]FDG-avid lymph nodes. Subsequent [18F]FES PET revealed single axillary lymph node metastasis in the vaccine-associated [18F]FDG-avid lymph nodes. To the best of our knowledge, this is the first study showing the usefulness of [18F]FES PET in diagnosing axillary lymph node metastasis in COVID-19-vaccinated patients harboring ER-positive breast cancer. Thus, [18F]FES PET has potential applications in the detection of true-positive metastatic lymph nodes in patients with ER-positive breast cancer regardless of the ipsilateral or contralateral side, who have received COVID-19 vaccination.

Feasibility of Renal Blood Flow Measurement Using 64Cu-ATSM PET/MRI: A Quantitative PET and MRI Study.

This study aimed to evaluate the renal blood flow (RBF) in patients with chronic kidney disease (CKD) using 64Cu(II)-diacetyl-bis(4-methylthiosemicarbazonate) (64Cu-ATSM) for positron emission tomography (PET)/magnetic resonance imaging (MRI). We included five healthy controls (HCs) and ten patients with CKD. The estimated glomerular filtration rate (eGFR) was calculated from the serum creatinine (cr) and cystatin C (cys) levels. The estimated RBF (eRBF) was calculated using the eGFR, hematocrit, and filtration fraction. A single dose of 64Cu-ATSM (300-400 MBq) was administered for RBF evaluation, and a 40 min dynamic PET scan was performed with simultaneous arterial spin labeling (ASL) imaging. PET-RBF images were obtained from the dynamic PET images at 3 min after injection using the image-derived input function method. The mean eRBF values calculated from various eGFR values differed significantly between the patients and HCs; both groups also differed significantly in terms of the RBF values (mL/min/100 g) measured using PET (151 ± 20 vs. 124 ± 22, p < 0.05) and ASL-MRI (172 ± 38 vs. 125 ± 30, p < 0.001). The ASL-MRI-RBF was positively correlated with the eRBFcr-cys (r = 0.858, p < 0.001). The PET-RBF was positively correlated with the eRBFcr-cys (r = 0.893, p < 0.001). The ASL-RBF was positively correlated with the PET-RBF (r = 0.849, p < 0.001). 64Cu-ATSM PET/MRI demonstrated the reliability of PET-RBF and ASL-RBF by comparing them with eRBF. This is the first study to demonstrate that 64Cu-ATSM-PET is useful for assessing the RBF and is well correlated with ASL-MRI.

Quantitative Assessment of Bone Marrow Activity Using 18 F-FLT PET in Aplastic Anemia and Myelodysplastic Syndromes.

PURPOSE: Peripheral cytopenias are typical of blood test abnormalities associated with a variety of conditions, including aplastic anemia (AA) and myelodysplastic syndromes (MDSs). We prospectively investigated the feasibility of quantitative analysis of whole-body bone marrow activity using PET with 3'-deoxy-3'- 18 F-fluorothymidine ( 18 F-FLT) in AA and MDS. PATIENTS AND METHODS: Sixty-eight patients with cytopenia underwent 18 F-FLT PET/MRI scan, with simultaneous bone marrow aspiration and biopsy for hematopoiesis evaluation. SUVs were measured in the vertebrae (Th3, 6, and 9 and L3), bilateral iliac crests, and extremities. SUV and bone marrow pathology were compared between AA and MDS and analyzed in relation to severity of AA and prognosis of MDS. RESULTS: Of the 68 patients with cytopenia, 12 were diagnosed with AA, 27 with MDS, 12 with bone marrow neoplasia, 2 with myelofibrosis, and 15 with other conditions. Iliac 18 F-FLT SUVs were significantly correlated with bone marrow cell numbers and cell density ( r = 0.47, P < 0.001 and ρ = 0.65, P < 0.001, respectively). There was a significant positive correlation between iliac and vertebral SUVs in AA and MDS ( r = 0.65, P < 0.05 and r = 0.70, P < 0.001, respectively), and the slope of the regression line was significantly steeper in AA than in MDS ( P < 0.05). In AA patients, vertebral 18 F-FLT SUVs significantly decreased with disease progression, and in MDS patients, higher whole-body 18 F-FLT uptake was associated with shorter overall survival (hazards ratio, 3.18; 95% confidence interval, 1.07-9.47; P = 0.037). CONCLUSIONS: Quantitative whole-body bone marrow imaging using 18 F-FLT PET helps distinguish AA from MDS and assess the severity of AA and prognosis of MDS.

Radiobrominated probe targeting activated p38α in inflammatory diseases.

OBJECTIVE: p38α, a member of the mitogen-activated protein kinase superfamily, is activated by external stimuli, followed by nuclear translocation for the regulation of inflammatory responses at the transcriptional and translational levels in inflammatory diseases. Thus, activated p38α would be an appropriate target molecule for in vivo noninvasive imaging and targeted radionuclide therapy. For this purpose, we designed a radiobrominated compound, 6-(4-[77Br]bromo-2-fluorophenoxy)-8-methyl-2-(tetrahydro-2H-pyran-4-ylamino)-pyrido[2,3-d]pyrimidin-7(8H)-one ([77Br]4-BR), based on a potent p38α selective inhibitor, R1487, for use with single-photon emission computed tomography. We synthesized [77Br]4-BR and evaluated its effectiveness as an activated p38α imaging probe compared with our previous radioiodinated probe (6-(2-fluoro-4-[125I]iodophenoxy)-8-methyl-2-(tetrahydro-2H-pyran-4-ylamino)-pyrido[2,3-d]pyrimidin-7(8H)-one ([125I]4-IR)) in a mouse inflammatory model. METHODS: We designed [77Br]4-BR by replacing the radioiodine of [125I]4-IR or the fluorine of R1487 with radiobromine at the 4-position of the phenoxy ring. We synthesized 4-BR via a four-step process. The inhibitory potency of 4-BR was measured using an ADP-Glo™ kinase assay system. Radiosynthesis of [77Br]4-BR was performed via an organotin-radiobromine exchange reaction using the corresponding tributyltin precursor. Radioactivity biodistribution was evaluated in normal ddY mice and turpentine oil-induced inflammation model mice for 120 min after intravenous administration of [77Br]4-BR. The temporal changes in radioactivity in blood fractions were compared between [77Br]4-BR and [125I]4-IR. RESULTS: 4-BR was synthesized at a total yield of 9.1% and showed a p38α inhibitory potency similar to that of 4-IR. [77Br]4-BR was successfully obtained from a tributyltin precursor with high radiochemical yield (89.9%), purity (95.9%), and molar activity (2.0 TBq/µmol). [77Br]4-BR showed accumulation of high radioactivity in the inflamed tissue (3.4% ± 0.9% ID/g, peaking at 15 min), rapid delivery throughout the body, and rapid blood clearance with approximately half of the blood radioactivity existing as an intact form at 60 min. Although the maximum radioactivity accumulation in inflamed tissue after [77Br]4-BR administration was approximately half that of [125I]4-IR because of its faster blood clearance and lower free fraction in the input function, the inflamed tissue-to-blood ratio was comparable between [77Br]4-BR and [125I]4-IR. CONCLUSIONS: [77Br]4-BR would be a promising imaging agent for detecting activated p38α in inflammatory diseases.

PET Imaging of Estrogen Receptors for Gynecological Tumors.

ABSTRACT: In the past few decades, PET with 18F-FDG has been used for the diagnosis of gynecological malignancies and is considered to be superior to conventional imaging methods in diagnostic accuracy for detecting metastatic lesions and local recurrence and in evaluating the treatment response. On the other hand, several gynecological tumors, such as endometrial cancer and leiomyoma, and breast cancer are estrogen-dependent, in which estrogen is essential for their development and progression. 18F-FES is an 18F-labeled compound of estradiol, the most bioactive type of estrogen, and 18F-FES PET has been well-established for diagnosis, staging, and posttherapeutic follow-up in patients with estrogen receptor-positive breast cancer. Compared with in vitro assessment of tumor biopsy material, PET imaging has the advantages of being able to measure in vivo tumor behavior, characterize the entire tumor burden, and capture the heterogeneity of the tumor phenotype. In this article, we review the phenotyping of estrogen-related gynecological tumors other than breast cancer using 18F-FES PET and demonstrate the additional value of 18F-FES PET to 18F-FDG PET in their diagnosis and prognostication. Moreover, promising PET tracers other than 18F-FES and 18F-FDG for the evaluation of estrogen-related gynecological tumors are introduced.

Cerebral Oxidative Stress in Early Alzheimer's Disease Evaluated by 64Cu-ATSM PET/MRI: A Preliminary Study.

Oxidative stress imaging using diacetyl-bis (N4-methylthiosemicarbazone) (Cu-ATSM) was applied to the evaluation of patients with early Alzheimer's disease (eAD). Ten eAD patients (72 ± 9 years) and 10 age-matched healthy controls (HCs) (73 ± 9 years) participated in this study. They underwent dynamic PET/MRI using 11C-PiB and 64Cu-ATSM with multiple MRI sequences. To evaluate cerebral oxidative stress, three parameters of 64Cu-ATSM PET were compared: standardized uptake value (SUV), tracer influx rate (Kin), and a rate constant k3. The input functions were estimated by the image-derived input function method. The relative differences were analyzed by statistical parametric mapping (SPM) using SUV and Kin images. All eAD patients had positive and HC subjects had negative PiB accumulation, and MMSE scores were significantly different between them. The 64Cu-ATSM accumulation tended to be higher in eAD than in HCs for both SUV and Kin. When comparing absolute values, eAD patients had a greater Kin in the posterior cingulate cortex and a greater k3 in the hippocampus compared with lobar cortical values of HCs. In SPM analysis, eAD had an increased left operculum and decreased bilateral hippocampus and anterior cingulate cortex compared to HCs. 64Cu-ATSM PET/MRI and tracer kinetic analysis elucidated cerebral oxidative stress in the eAD patients, particularly in the cingulate cortex and hippocampus.

Development of Low Molecular Weight Ligands for Integrin αvß3.

We designed and synthesized non-peptide organic molecular ligands for integrin αvß3. Candidate ligands featured amidino analog and carboxy groups as binding sites on either side of a spacer, which consisted of benzophenone or an analog, such as diphenyl sulfide, diphenyl sulfoxide, diphenyl sulfone, or diphenyl ether. Competitive binding assays to integrin αvß3 with respect to [125I]echistatin were used to determine inhibitory activity of the synthetic ligands. Ligands bearing 2-aminobenzimidazoyl and glycyl groups separated by a benzophenone spacer demonstrated more potent binding than did a linear Arg-Gly-Asp (RGD) tripeptide that represents the native integrin αvß3 binding motif. Ligands possessing 2-aminobenzimidazoyl and carboxy groups and diphenyl sulfoxide or diphenyl ether spacers inhibited binding of [125I]echistatin with IC50 values similar to that of the linear RGD tripeptide.

Development of Radiohalogenated Osimertinib Derivatives as Imaging Probes for Companion Diagnostics of Osimertinib.

Osimertinib is an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor approved for treating non-small-cell lung cancer (NSCLC) with EGFR mutations. Genetic testing is required to detect the mutation for selecting patients who can use osimertinib. Here, we report an attempt to develop nuclear imaging probes that detect the EGFR mutations. We designed and synthesized I-osimertinib and Br-osimertinib with a radioactive or nonradioactive halogen atom at an indole ring in osimertinib and evaluated them. In vitro assays suggested that both I-osimertinib and Br-osimertinib exhibit a specifically high activity toward NSCLC with EGFR L858R/T790M mutations. In biodistribution experiments, the accumulation of both [125I]I-osimertinib and [77Br]Br-osimertinib in tumors with mutations was significantly higher than that in blood and muscle. However, these osimertinib derivatives showed a significantly higher accumulation in lungs than in tumors. Therefore, for detecting the mutations in lung cancer, further structural modifications of the probes are required.

Evaluation of (R)-[11C]PK11195 PET/MRI for Spinal Cord-Related Neuropathic Pain in Patients with Cervical Spinal Disorders.

Activated microglia are involved in secondary injury after acute spinal cord injury (SCI) and in development of spinal cord-related neuropathic pain (NeP). The aim of the study was to assess expression of translocator protein 18 kDa (TSPO) as an indicator of microglial activation and to investigate visualization of the dynamics of activated microglia in the injured spinal cord using PET imaging with (R)-[11C]PK11195, a specific ligand for TSPO. In SCI chimeric animal models, TSPO was expressed mainly in activated microglia. Accumulation of (R)-[3H]PK11195 was confirmed in autoradiography and its dynamics in the injured spinal cord were visualized by (R)-[11C]PK11195 PET imaging in the acute phase after SCI. In clinical application of (R)-[11C]PK11195 PET/MRI of the cervical spinal cord in patients with NeP related to cervical disorders, uptake was found in cases up to 10 months after injury or surgery. No uptake could be visualized in the injured spinal cord in patients with chronic NeP at more than 1 year after injury or surgery, regardless of the degree of NeP. However, a positive correlation was found between standardized uptake value ratio and the severity of NeP, suggesting the potential of clinical application for objective evaluation of chronic NeP.

Metastatic invasive lobular breast cancer presenting as linitis plastica of the colon: Tumour characterization using [18 F]FES PET/MRI.

Metastatic invasive lobular breast cancer (ILC) to the colon is rare and usually ER-positive. We present an ER-negative case of metastatic ILC presenting as linitis plastica of the colon where [18 F]FES PET/MRI allowed the evaluation of the ER phenotypic transformation in the colonic metastasis from the ER-positive breast ILC in vivo.

Assessing the ADC of Bone-marrow on Whole-body MR Images in Relation to the Fat-suppression Method and Fat Content.

PURPOSE: To compare apparent diffusion coefficients (ADCs) of bone marrow on diffusion-weighted imaging (DWI) between two fat-suppression techniques, and to evaluate the association between bone-marrow ADCs and the proton density fat fraction (PDFF). METHODS: Seventy-seven patients underwent whole-body DWI with short-inversion time inversion-recovery (STIR) (DWISTIR) and/or STIR + selective water-excitation (spectral-spatial RF [SSRF]) (DWISTIR+SSRF). ADCs of lumbar vertebrae (L3 and L4) were compared between DWISTIR and DWISTIR+SSRF, and correlated with the PDFF. RESULTS: Lumbar ADCs obtained by DWISTIR and DWISTIR+SSRF were significantly correlated (L3: r = 0.90, P < 0.0001, L4: r = 0.90, P < 0.0001). Lumbar ADCs (× 10-6 mm2/s) obtained by DWISTIR were significantly lower than those by DWISTIR+SSRF (L3: 479 ± 137 and 490 ± 148, P < 0.05, L4: 456 ± 114 and 471 ± 118, P < 0.005). Residual fat signals were more clearly observed on DWISTIR than on DWISTIR+SSRF. The ADCs of L3 obtained by DWISTIR and DWISTIR+SSRF exhibited significant positive correlations with the PDFF (r = 0.51, P < 0.0001, and r = 0.45, P < 0.0001, respectively), and the ADCs of L4 obtained by DWISTIR and DWISTIR+SSRF exhibited significantly positive correlations with the PDFF (r = 0.40, P < 0.0005, and r = 0.40, P < 0.0005, respectively). CONCLUSION: Irrespective of different fat-suppression methods, lumbar ADCs were positively correlated with the PDFF, being inconsistent with previous studies. Lumbar ADCs obtained by DWISTIR were significantly lower than those obtained by DWISTIR+SSRF, probably due to residual fat signals on DWISTIR. However, this difference (< 4%) did not explain the positive correlation between lumbar ADC and PDFF.

Utilization of Antibody Allows Rapid Clearance of Nanoparticle Probes from Blood without the Need of Probe Modifications.

Nanoparticles are attracting attention as drug carriers for realizing "theranostics". However, nanoparticles generally show long blood circulation behaviors, and the remaining nanoparticle probe in the blood is the cause of prolonged optimal time from probe injection to imaging. Recently, it has been reported that some nanoparticles activate the immune system, producing an anti-nanoparticle antibody, which can selectively detect the corresponding nanoparticle and transfer it to the liver by opsonization. Lactosome is a polymer micelle prepared from amphiphilic PNMG-block-PLLA polydepsipeptide and known to activate the immune system when administered to mice at a specific concentration. In this study, radioactive fluorine-labeled lactosome (18F-lactosome) is used as a positron emission tomography probe for tumor imaging, and anti-lactosome antibody was additionally administrated after 2 h from the probe dosage. 18F-lactosome remaining in the blood was opsonized by the anti-lactosome antibody and transferred to the liver under the antibody dose-dependent manner. Because of the probe reduction from the blood, the tumor/blood signal intensity ratio could be improved up to 50% by anti-lactosome antibody administration. There needs further improvement, but the developed method is applicable for imaging utilizing nanoparticle probes, which activate the immune system.

18F-Fluoroestradiol Tumor Uptake Is Influenced by Structural Components in Breast Cancer.

PURPOSE: Estrogen receptor (ER) is expressed in the majority of invasive breast cancer and is an important prognostic indicator. The tumor stroma also plays an important role in disease progression. This study evaluated the effect of stromal components on 16α-[18F]-fluoro-17ß-estradiol (18F-FES) uptake in breast cancer and proposed a partial-volume correction method for 18F-FES PET based on histopathological analyses. PATIENTS AND METHODS: Fifteen patients with biopsy-confirmed breast cancer underwent preoperative 18F-FES PET. Estrogen receptor expression in biopsy specimens was assayed by immunohistochemistry, cellular components in surgical specimens were measured using hematoxylin-eosin staining, and nuclear components in surgical and biopsy specimens were measured using Azan-Mallory staining. The relationship between 18F-FES SUV of the primary tumor and histopathological findings including ER expression, the Allred score, ER-positive cellular component ratio, and ER-positive nuclear component ratio (NCR) was examined. The relationship between stroma-free 18F-FES SUV and ER expression was also examined. RESULTS: 18F-FES uptake was not significantly positively correlated with ER expression (r = 0.44, P = 0.10). 18F-FES uptake was significantly correlated with the Allred score, ER-positive cellular component ratio, and ER-positive NCR in surgical specimens (ρ = 0.60, P = 0.02; r = 0.55, P = 0.03; and r = 0.65, P = 0.01, respectively). 18F-FES uptake was predominantly correlated with ER-positive NCR in biopsy specimens (r = 0.84, P < 0.001). Stroma-free 18F-FES SUV was significantly correlated with ER expression (r = 0.78, P < 0.01). CONCLUSIONS: 18F-FES PET predominantly demonstrates the level of ER expression in breast cancer cell nucleus. Although tumor 18F-FES uptake is affected by the degree of stromal components, the partial volume effect on the uptake can be corrected by stroma-volume fraction in Azan-Mallory staining.

Predictive value of 3'-deoxy-3'-18F-fluorothymidine PET in the early response to anti-programmed death-1 therapy in patients with advanced non-small cell lung cancer.

BACKGROUND: Anti-programmed death-1 (anti-PD-1) therapy has shown clinical success in patients with advanced non-small cell lung cancer (NSCLC). However, it is difficult to evaluate the early response to anti-PD-1 therapy. We determined whether changes in 3'-deoxy-3'-[18F]-fluorothymidine (18F-FLT) PET parameters before and soon after treatment initiation predicted the therapeutic effect of anti-PD-1 antibody. METHODS: Twenty-six patients with advanced NSCLC treated with anti-PD-1 antibody were enrolled prospectively and underwent 18F-FLT PET before and at 2 and 6 weeks after treatment initiation. Changes in maximal standardized uptake value (ΔSUVmax), proliferative tumor volume (ΔPTV) and total lesion proliferation (ΔTLP) of the lesions were calculated and evaluated for their associations with the clinical response to therapy. RESULTS: The disease control rate was 64%. Patients with non-progressive disease (non-PD) had significantly decreased TLP at 2 weeks, and decreased SUVmax, PTV, and TLP at 6 weeks, compared with those with PD, while three of eight (37.5%) patients who responded had increased TLP from baseline at 2 weeks (ie, pseudoprogression). Among the parameters that changed between baseline and 2 weeks, ΔPTV0-2 and ΔTLP0-2 had the highest accuracy (76.0%) to predict PD. Among the parameters that changed between baseline and 6 weeks, ΔSUVmax0-6, ΔPTV0-6 and ΔTLP0-6 had the highest accuracy (90.9%) to predict PD. ΔTLP0-2 (≥60%, HR 3.41, 95% CI 1.34-8.65, p=0.010) and ΔTLP0-6 (≥50%, HR 31.4, 95% CI 3.55 to 276.7, p=0.0019) were indicators of shorter progression-free survival. CONCLUSIONS: Changes in 18F-FLT PET parameters may have value as an early predictive biomarker for the response to anti-PD-1 therapy in patients with NSCLC. However, it should be noted that pseudoprogression was observed in 18F-FLT PET imaging at 2 weeks after treatment initiation. TRIAL REGISTRATION NUMBER: jRCTs051180147.

Paradoxical changes in mood-related behaviors on continuous social isolation after weaning.

Continuous social isolation (SI) from an early developmental stage may have different effects in youth and adulthood. Moreover, SI is reported to impair neuronal plasticity. In this study, we used post-weaning rats to compare the impact of continuous SI on depressive-like, anxiety-related, and fear-related behaviors and neuronal plasticity in puberty and adulthood. Furthermore, we assessed the effect of lithium on behavioral changes and neuronal plasticity. Continuous SI after weaning induced depressive-like behaviors in puberty; however, in adulthood, depressive-like and anxiety-related behaviors did not increase, but-paradoxically-decreased in comparison with the controls. The decreased expression of neuronal plasticity-related proteins in the hippocampus in puberty was more prominent in the prefrontal cortex and hippocampus in adulthood. In contrast, SI after weaning tended to decrease fear-related behaviors in puberty, a decrease which was more prominent in adulthood with increased neuronal plasticity-related protein expression in the amygdala. Lithium administration over the last 14 days of the SI-induced period removed the behavioral and expression changes of neuronal plasticity-related proteins observed in puberty and adulthood. Our findings suggest that the extension of the duration of SI from an early developmental stage does not simply worsen depressive-like behaviors; rather, it induces a behavior linked to neuronal plasticity damage. Lithium may improve behavioral changes in puberty and adulthood by reversing damage to neuronal plasticity. The mechanisms underlying the depressive-like and anxiety-related behaviors may differ from those underlying fear-related behaviors.

A Radiobrominated Tyrosine Kinase Inhibitor for EGFR with L858R/T790M Mutations in Lung Carcinoma.

Activating double mutations L858R/T790M in the epidermal growth factor receptor (EGFR) region are often observed as the cause of resistance to tyrosine kinase inhibitors (TKIs). Third-generation EGFR-TKIs, such as osimertinib and rociletinib (CO-1686), was developed to target such resistance mutations. The detection of activating L858R/T790M mutations is necessary to select sensitive patients for therapy. Hence, we aimed to develop novel radiobromine-labeled CO-1686 as a positron emission tomography (PET) imaging probe for detecting EGFR L858R/T790M mutations. Nonradioactive brominated-CO1686 (BrCO1686) was synthesized by the condensation of N-(3-[{2-chloro-5-(trifluoromethyl)pyrimidin-4-yl}amino]-5-bromophenyl) acrylamide with the corresponding substituted 1-(4-[4-amino-3-methoxyphenyl]piperazine-1-yl)ethan-1-one. The radiobrominated [77Br]BrCO1686 was prepared through bromodestannylation of the corresponding tributylstannylated precursor with [77Br]bromide and N-chlorosuccinimide. Although we aimed to provide a novel PET imaging probe, 77Br was used as an alternative radionuclide for 76Br. We fundamentally evaluated the potency of [77Br]BrCO1686 as a molecular probe for detecting EGFR L858R/T790M using human non-small-cell lung cancer (NSCLC) cell lines: H1975 (EGFR L858R/T790M), H3255 (EGFR L858R), and H441 (wild-type EGFR). The BrCO1686 showed high cytotoxicity toward H1975 (IC50 0.18 ± 0.06 µM) comparable to that of CO-1686 (IC50 0.14 ± 0.05 µM). In cell uptake experiments, the level of accumulation of [77Br]BrCO1686 in H1975 was significantly higher than those in H3255 and H441 upon 4 h of incubation. The radioactivity of [77Br]BrCO1686 (136.3% dose/mg protein) was significantly reduced to 56.9% dose/mg protein by the pretreatment with an excess CO-1686. These results indicate that the binding site of the radiotracers should be identical to that of CO-1686. The in vivo accumulation of radioactivity of [77Br]BrCO1686 in H1975 tumor (4.51 ± 0.17) was higher than that in H441 tumor (3.71 ± 0.13) 1 h postinjection. Our results suggested that [77Br]BrCO1686 has specificity toward NSCLC cells with double mutations EGFR L858R/T790M compared to those in EGFR L858R and wild-type EGFR. However, the in vivo accumulation of radioactivity in the targeted tumor needs to be optimized by structural modification.

Prognostic Value of 16α-18F-Fluoro-17ß-Estradiol PET as a Predictor of Disease Outcome in Endometrial Cancer: A Prospective Study.

The purpose of this study was to evaluate the potential of 16α-18F-fluoro-17ß-estradiol (18F-FES) PET to predict prognosis in patients with endometrial cancer (EC). Methods: In total, 67 patients with International Federation of Gynecology and Obstetrics (FIGO) stage I-IV EC underwent 18F-FES and 18F-FDG PET/CT before treatment. The SUVmean of the primary tumor was compared with the clinical characteristics, and the relationships between SUV and progression-free survival (PFS) or overall survival were analyzed. Results:18F-FES SUV was significantly associated with stage, histology, lymphovascular space involvement (LVSI), and lymph node metastasis, and 18F-FDG SUV was significantly associated with stage, myometrial invasion, tumor size, and lymph node metastasis. Receiver-operating characteristic curve analysis revealed that 18F-FES SUV could significantly detect tumor progression and survival, with areas under the curve of 0.813 and 0.790, respectively, whereas 18F-FDG SUV could detect them with areas under the curve of 0.557 and 0.635, respectively. The Kaplan-Meier survival curve showed that patients with a low 18F-FES SUV had significantly poor PFS (P < 0.001) and overall survival (P = 0.001) compared with patients with a high SUV, whereas 18F-FDG showed no significant differences. In a subanalysis of 27 patients with a low risk of recurrence (FIGO stage IA endometrioid carcinoma [grade 1 or 2] without LVSI), those with a low 18F-FES SUV also had poorer PFS than those with a high SUV (P = 0.002). In multivariate analysis, an 18F-FES SUV of less than 2.63 (P = 0.037; hazard ratio, 10.727; 95% CI, 1.16-99.35) and FIGO stages III and IV (P = 0.042; hazard ratio, 8.838; 95% CI, 1.09-71.84) were significantly associated with PFS. Conclusion: A low 18F-FES for the primary tumor was strongly associated with prognostic factors of EC such as LVSI and lymph node metastasis, and a low 18F-FES SUV was an independent prognostic factor for PFS in patients with EC. These data suggest that pretreatment 18F-FES PET might be useful in determining the appropriate treatment for patients with EC.