Changes in In-Hospital Survival and Long-Term Neurodevelopmental Outcomes of Extremely Preterm Infants: A Retrospective Study of a Japanese Tertiary Center.

OBJECTIVES: The objective of this study was to elucidate whether the survival and long-term neurodevelopmental outcomes of extremely preterm infants have improved in a Japanese tertiary center with an active treatment policy for infants born at 22-23 weeks of gestation. STUDY DESIGN: This single-centered retrospective cohort study enrolled extremely preterm infants treated at Saitama Medical Center, Saitama Medical University, from 2003 to 2014. Patients with major congenital abnormalities were excluded. Primary outcomes were in-hospital survival and severe neurodevelopmental impairment (NDI) at 6 years of age, which was defined as having severe cerebral palsy, severe cognitive impairment, severe visual impairment, or deafness. We assessed the changes in primary outcomes between the first (period 1; 2003-2008) and the second half (period 2; 2009-2014) of the study period and evaluated the association between birth-year and primary outcomes using multivariate logistic regression models. RESULTS: Of the 403 eligible patients, 340 (84%) survived to discharge. Among 248 patients available at 6 years of age, 43 (14%) were classified as having severe NDI. Between the 2 periods, in-hospital survival improved from 155 of 198 (78%) to 185 of 205 (90%), but severe NDI increased from 11 of 108 (10%) to 32 of 140 (23%). In multivariate logistic regression models adjusted for gestational age, birthweight, sex, singleton birth, and antenatal corticosteroids, the aOR (95% CI) of birth-year for in-hospital survival and severe NDI was 1.2 (1.1-1.3) and 1.1 (1.0-1.3), respectively. CONCLUSION: Mortality among extremely preterm infants has improved over the past 12 years; nevertheless, no significant improvement was observed in the long-term neurodevelopmental outcomes.

Therapeutic response of iNO in preterm infants with hypoxemic respiratory failure.

BACKGROUND: Inhaled nitric oxide (iNO) has been used as a rescue treatment for preterm infants with hypoxemic respiratory failure (HRF). However, its effectiveness remains debatable. Thus, in this study, we aimed to examine the impact of iNO therapy on HRF in extremely preterm infants. METHODS: A retrospective observational study was performed. Extremely preterm infants admitted to our neonatal intensive care unit who received iNO therapy later in their postnatal life were included. The oxygen saturation index (OSI) was used as an index of the severity of respiratory failure. RESULTS: In total, 30 extremely preterm infants were included in this study. Oxygenation was enhanced after the administration of iNO in infants with HRF. The OSI decreased by more than 20% in 12 patients (40%, positive responder) and did not decrease in 17 patients (57%, negative responder) within the first 6 h of treatment. The iNO initiation day was the significant independent factor associated with a positive response to iNO therapy in extremely preterm infants with HRF. CONCLUSIONS: iNO therapy was effective in enhancing oxygenation in extremely preterm infants with HRF. Earlier use of iNO was the significant factor associated with a positive therapeutic response to iNO, implying that iNO may be more effective in pulmonary vessels which are less damaged by shorter-term mechanical ventilation.

Randomized Trial of Perfusion-Based Circulatory Management in Infants of Very Low Birth Weight.

OBJECTIVE: To establish the superiority of blood flow (BF)-based circulatory management over conventional blood pressure (BP)-based management strategies used for preventing intraventricular hemorrhage (IVH) in infants of very low birth weight (VLBW). STUDY DESIGN: We conducted a nonblinded, single-centered randomized trial with the aim to prevent IVH by managing BF. Infants with VLBW were assigned randomly to a BF-based group or BP-based (BP group) circulatory management group. The incidence of IVH was the outcome of interest. The IVH also data were compared among healthy patients and patients responsive and unresponsive to the intervention. RESULTS: A total of 219 and 220 infants with VLBW were assigned to the BF and BP groups, respectively. The IVH incidence rate was lower in the BF group, but the difference was not statistically significant (BF group, 6.8% vs BP group, 10.9%; P = .14). In 21% of patients of the BP group and 20% of the BF group, the intervention failed. In BF group, the IVH incidence rate was significantly greater in infants with unsuccessful intervention when compared with healthy individuals (6% vs 23%, P = .001). Multivariate logistic regression analysis revealed a correlation between low blood flow and IVH (aOR 3.24; 95% CI 1.49-7.08, P = .003) but not between low BP and IVH (P = .73). CONCLUSIONS: The BF management protocol did not significantly decrease the incidence of IVH. However, after further optimization, we speculate the treatment strategy holds promise in decreasing the incidence of IVH. Trial registration UMIN-CTR: UMIN000013296.

Successful Percutaneous Thrombectomy of the Left Pulmonary Artery in a Neonate After a Patent Ductus Arteriosus Clipping.

We report a neonate with a successful percutaneous thrombectomy of a total thrombotic occlusion of the left pulmonary artery (LPA) after a surgical clipping for a patent ductus arteriosus (PDA). We suspected the compression of the LPA by the clipping and postoperative hemodynamic instability caused the LPA obstruction. After the surgical removal of the PDA clip and division of the PDA, we could safely retrieve the LPA thrombus with a non-hydrodynamic thrombectomy catheter for coronary arteries.

Fasting Enhances the Contrast of Bone Metastatic Lesions in 18F-Fluciclovine-PET: Preclinical Study Using a Rat Model of Mixed Osteolytic/Osteoblastic Bone Metastases.

18F-fluciclovine (trans-1-amino-3-18F-fluorocyclobutanecarboxylic acid) is an amino acid positron emission tomography (PET) tracer used for cancer staging (e.g., prostate and breast). Patients scheduled to undergo amino acid-PET are usually required to fast before PET tracer administration. However, there have been no reports addressing whether fasting improves fluciclovine-PET imaging. In this study, the authors investigated the influence of fasting on fluciclovine-PET using triple-tracer autoradiography with 14C-fluciclovine, [5,6-³H]-2-fluoro-2-deoxy-d-glucose (³H-FDG), and 99mTc-hydroxymethylene diphosphonate (99mTc-HMDP) in a rat breast cancer model of mixed osteolytic/osteoblastic bone metastases in which the animals fasted overnight. Lesion accumulation of each tracer was evaluated using the target-to-background (muscle) ratio. The mean ratios of 14C-fluciclovine in osteolytic lesions were 4.6 ± 0.8 and 2.8 ± 0.6, respectively, with and without fasting, while those for ³H-FDG were 6.9 ± 2.5 and 5.1 ± 2.0, respectively. In the peri-tumor bone formation regions (osteoblastic), where 99mTc-HMDP accumulated, the ratios of 14C-fluciclovine were 4.3 ± 1.4 and 2.4 ± 0.7, respectively, and those of ³H-FDG were 6.2 ± 3.8 and 3.3 ± 2.2, respectively, with and without fasting. These results suggest that fasting before 18F-fluciclovine-PET improves the contrast between osteolytic and osteoblastic bone metastatic lesions and background, as well as 18F-FDG-PET.

Use of high-flow nasal cannula in neonates: Nationwide survey in Japan.

High-flow nasal cannula is a new modality of respiratory support and is increasing in popularity despite the lack of supporting evidence. We investigated the prevalence of its use in tertiary neonatal units in Japan. A paper-based survey was conducted. The response rate was 83%. High-flow nasal cannula was used in 46/80 units (58%), of which 96% used the high-flow nasal cannula without guidelines. It was used for several indications, including weaning off nasal continuous positive airway pressure and post-extubation respiratory support. The main perceived benefits of the cannula included better access to the neonate and reduced risk of nasal trauma. This survey found that high-flow nasal cannula is used without clear criteria and that clinical practice varies across neonatal units in Japan. Its use in neonates needs to be urgently evaluated.

Assessment of Amino Acid/Drug Transporters for Renal Transport of [18F]Fluciclovine (anti-[18F]FACBC) in Vitro.

[18F]Fluciclovine (trans-1-amino-3-[18F]fluorocyclobutanecarboxylic acid; anti-[18F]FACBC), a positron emission tomography tracer used for the diagnosis of recurrent prostate cancer, is transported via amino acid transporters (AATs) with high affinity (Km: 97-230 µM). However, the mechanism underlying urinary excretion is unknown. In this study, we investigated the involvement of AATs and drug transporters in renal [18F]fluciclovine reuptake. [14C]Fluciclovine (trans-1-amino-3-fluoro[1-14C]cyclobutanecarboxylic acid) was used because of its long half-life. The involvement of AATs in [14C]fluciclovine transport was measured by apical-to-basal transport using an LLC-PK1 monolayer as model for renal proximal tubules. The contribution of drug transporters herein was assessed using vesicles/cells expressing the drug transporters P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), multidrug resistance-associated protein 4 (MRP4), organic anion transporter 1 (OAT1), organic anion transporter 3 (OAT3) , organic cation transporter 2 (OCT2), organic anion transporting polypeptide 1B1 (OATP1B1), and organic anion transporting polypeptide 1B3 (OATP1B3). The apical-to-basal transport of [14C]fluciclovine was attenuated by l-threonine, the substrate for system alanine-serine-cysteine (ASC) AATs. [14C]Fluciclovine uptake by drug transporter-expressing vesicles/cells was not significantly different from that of control vesicles/cells. Fluciclovine inhibited P-gp, MRP4, OAT1, OCT2, and OATP1B1 (IC50 > 2.95 mM). Therefore, system ASC AATs may be partly involved in the renal reuptake of [18F]fluciclovine. Further, given that [18F]fluciclovine is recognized as an inhibitor with millimolar affinity for the tested drug transporters, slow urinary excretion of [18F]fluciclovine may be mediated by system ASC AATs, but not by drug transporters.

Peripheral blood flow monitoring in an infant with septic shock.

Septic shock is associated with impaired vasoregulation, and treatment includes vasoactive drugs. Therefore, evaluation of vasoregulatory change is important. The present report describes the successful characterization of vasoregulatory change in response to a vasoactive drug during septic shock. A male infant born at 23 weeks' gestation developed septic shock. Severe hypotension developed, and treatment with colloid fluid and dopamine failed to increase blood pressure. With continuous measurement of skin blood flow using laser Doppler, noradrenaline was started. Based on changes in the blood flow, the dose was increased. At a dose of 1 µg/kg per min, skin blood flow in the foot decreased without any change in blood pressure. Subsequent blood transfusion succeeded in increasing both blood pressure and skin blood flow. It is concluded that decrease in foot blood flow reflects the vasoconstrictive effect of noradrenaline, although this finding must be validated in larger studies.

Safety and feasibility of a factory-calibrated continuous glucose monitoring system in term and near-term infants at risk of hypoglycemia.

OBJECTIVE: Hypoglycemia increases the risk of adverse neurological outcomes in neonates. Adequate glucose monitoring requires repetitive and painful blood sampling. We aimed to evaluate the feasibility and accuracy of a continuous glucose monitoring system (CGMS) using factory-calibrated sensors to improve glucose monitoring and decrease the frequency of blood samples in neonates. MATERIAL AND METHODS: A methodological study was conducted to investigate a correlation of CGMS values with blood glucose measurements. RESULTS: Factory-calibrated CGMS sensors were placed on 21 infants at risk of hypoglycemia after delivery. CGMS values were compared with blood glucose concentrations. Thirty-seven pairs of CGMS and blood glucose values were obtained. There was a good correlation between CGMS and blood glucose values (R=0.67, p<0.01) with a mean difference (2 standard deviations) of 9.78 (-24.68 to 44.25) mg/dL. The mean differences at <3 hours and ≥3 hours after sensor placement were 17.35 (-4.54 to 39.21) mg/dL and 0.88 (-37.62 to 39.38) mg/dL, respectively. CGMS values were significantly higher than blood glucose concentration at <3 hours after sensor placement (p<0.01), whereas no significant differences in glucose values were observed between the CGMS and blood glucose values at ≥3 hours after sensor placement (p=0.852). CONCLUSION: The factory-calibrated CGMS was a safe and feasible modality for glucose monitoring. However, it has a tendency to overestimate the blood glucose concentrations. Therefore, this system should be used cautiously for neonates at risk of hypoglycemia, especially within 3 hours after sensor placement.

Extreme Prematurity and Pulmonary Outcomes Program in Saitama: Protocol for a Prospective Multicenter Cohort Study in Japan.

BACKGROUND: Because of the improvements in survival rates for preterm infants, not only the rates of bronchopulmonary dysplasia (BPD) but also those of long-term respiratory complications of premature birth are increasing, resulting in financial and health burdens in developed countries. Thus far, the risk factors of respiratory morbidities in extremely preterm infants remain unknown. Furthermore, the definition and the predictive ability of BPD for long-term respiratory outcomes are yet to be determined. OBJECTIVE: The objective of our study, Extreme Prematurity and Pulmonary Outcomes Program in Saitama, is to develop the diagnostic criteria for BPD and to determine the prognostic factors contributing to the long-term pulmonary outcomes manifesting in extremely preterm infants. METHODS: The Extreme Prematurity and Pulmonary Outcomes Program in Saitama is an observational prospective cohort study performed by a consortium of six neonatal intensive care units (NICUs) in Saitama, Japan. The subjects included in this study are infants (from each clinical center) with gestational ages 22 to 27 weeks. The target is 400 subjects. This study aims to determine the definition of BPD and other perinatal factors that accurately predict the long-term pulmonary outcomes in survivors of extreme prematurity. Moreover, the association between BPD and postprematurity respiratory disease will be investigated using generalized linear models. RESULTS: The protocol and consent forms were evaluated and approved on September 5, 2019, by the Ethics Committee of Saitama Medical Center, Saitama Medical University. Enrollment began on April 1, 2020. It is expected to end on March 31, 2023. The follow-up for 1 year corrected age is expected to continue through the middle of 2024. CONCLUSIONS: The Extreme Prematurity and Pulmonary Outcomes Program in Saitama incorporates aspects of neonatal care in secondary- and tertiary-level NICUs to develop existing research studies on the definition of BPD, objective biomarkers, and outcome measures of respiratory morbidity in extremely preterm infants beyond NICU hospitalization, thereby leading to a novel understanding of the nature and natural history of BPD and potential mechanistic and therapeutic targets in at-risk subjects. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/22948.

Randomized Controlled Trial of High-Flow Nasal Cannula in Preterm Infants After Extubation.

OBJECTIVES: Our aim is to compare the efficacy and safety of high-flow nasal cannula (HFNC) against those of nasal continuous positive airway pressure (NCPAP) or nasal intermittent positive-pressure ventilation (NIPPV) after extubation in preterm infants. METHODS: This prospective, randomized, noninferiority trial was conducted in 6 tertiary NICUs. Infants born at <34 weeks who needed noninvasive ventilation after extubation were enrolled. We randomly assigned infants to an HFNC group when HFNC was used or to an NCPAP/NIPPV group when NCPAP or NIPPV was used. The primary outcome was treatment failure within 7 days after extubation. We then examined clinical aspects of treatment failure with HFNC use. RESULTS: In total, 176 and 196 infants were assigned to the HFNC and NCPAP/NIPPV groups, respectively. The HFNC group showed a significantly higher rate of treatment failure than that of the NCPAP/NIPPV group, with treatment failure occurring in 54 infants (31%) compared with 31 infants (16%) in the NCPAP/NIPPV group (risk difference, 14.9 percentage points; 95% confidence interval, 6.2-23.2). Histologic chorioamnionitis (P = .02), treated patent ductus arteriosus (P = .001), and corrected gestational age at the start of treatment (P = .007) were factors independently related to treatment failure with HFNC use. CONCLUSIONS: We found HFNC revealed a significantly higher rate of treatment failure than NCPAP or NIPPV after extubation in preterm infants. The independent factors associated with treatment failure with HFNC use were histologic chorioamnionitis, treated patent ductus arteriosus, and a younger corrected gestational age at the start of treatment.

Two Extremely Low Birth Weight Infants Who Survived Functional Pulmonary Atresia with Normal Intracardiac Anatomy.

For the first time, we report about two extremely low birth weight infants who were born at 25 and 22 weeks' gestation and who survived functional pulmonary atresia (fPA) with normal intracardiac anatomy. A slow, reflected, and bimodal blood flow pattern in the pulmonary artery (both cases) and the presence of pulmonary regurgitation (1 case) were useful for diagnosing fPA. Timely use of lipo-prostaglandin E1 to maintain adequate pulmonary flow and reduce pulmonary arterial resistance and sodium bicarbonate to improve acidosis were effective treatments to attain forward flow. As optimal management is essential for the intact survival of extremely early preterm infants and the accurate diagnosis of fPA is difficult without the awareness of the disease entity, our cases underline the importance of recognizing that fPA can occur even in extremely low birth weight infants with normal intracardiac anatomy.

A preliminary study of anti-1-amino-3-18F-fluorocyclobutyl-1-carboxylic acid for the detection of prostate cancer.

UNLABELLED: We evaluated the feasibility of anti-1-amino-3-(18)F-fluorocyclobutyl-1-carboxylic acid (anti-(18)F-FACBC) in diagnosing prostate cancer (PCa), using a rat orthotopic prostate cancer transplantation (OPCT) model. Furthermore, using in vivo experiments, we examined the potential of anti-(18)F-FACBC for differentiating between PCa and inflammation and between PCa and benign prostatic hyperplasia (BPH). METHODS: The OPCT model was developed by transplanting DU145, a human PCa cell line, into the ventral prostate of athymic F344 rats. To develop a dual PCa and inflammation (DPCI) model, MAT-Ly-Lu-B2--a rat PCa cell line--was transplanted subcutaneously into male Copenhagen rats. Streptozotocin was injected into the hind footpad of these rats for inducing popliteal lymphadenitis. For inducing the BPH, normal F344 rats were castrated and injected subcutaneously with testosterone propionate. In biodistribution studies, the rats were injected with anti-(18)F-FACBC or (18)F-FDG and sacrificed at 15 or 60 min after injection. We performed dynamic small-animal PET of the abdominal portion of the OPCT rats for 60 min after the injection of anti-(18)F-FACBC or (18)F-FDG. RESULTS: The biodistribution in the OPCT rats at 60 min after injection showed that the uptake of anti-(18)F-FACBC and (18)F-FDG into the PCa tissue was 1.58 +/- 0.40 %ID/cm(3) (percentage injected dose per cm(3)) and 1.48 +/- 0.90 %ID/cm(3), respectively (P > 0.05). The accumulation of anti-(18)F-FACBC in the urinary bladder at 60 min after injection was 3.09 +/- 1.43 %ID/cm(3), whereas that of (18)F-FDG was 69.31 +/- 16.55 %ID/cm(3) (P < 0.05). Consequently, small-animal imaging with anti-(18)F-FACBC facilitated the visualization of the PCa tissue of the OPCT rats with higher contrast than (18)F-FDG. Furthermore, in comparison with (18)F-FDG, apparently higher ratios of PCa to inflammation and PCa to BPH accumulation of anti-(18)F-FACBC were demonstrated in the animal models. CONCLUSION: FACBC PET is believed to be useful not only for the visualization of human PCa but also for differentiating between PCa and inflammation and between PCa and BHP.

PET Tracer 18F-Fluciclovine Can Detect Histologically Proven Bone Metastatic Lesions: A Preclinical Study in Rat Osteolytic and Osteoblastic Bone Metastasis Models.

18F-Fluciclovine (trans-1-amino-3-18F-fluorocyclobutanecarboxylic acid; anti-18F-FACBC) is a positron emission tomography (PET) tracer for diagnosing cancers (e.g., prostate and breast cancer). The most frequent metastatic organ of these cancers is bone. Fluciclovine-PET can visualize bony lesions in clinical practice; however, such lesions have not been described histologically. Methods: We investigated the potential of 14C-fluciclovine in aiding the visualization of osteolytic and osteoblastic bone metastases (with histological analyses), compared with 3H-2-deoxy-2-fluoro-D-glucose (3H-FDG), 3H-choline chloride (3H-choline), and 99mTc-hydroxymethylene diphosphonate (99mTc-HMDP) by using triple-tracer autoradiography in rat breast cancer osteolytic (on day 12 ± 1 postinjection of MRMT-1) and prostate cancer osteoblastic (on day 20 ± 3 postinjection of AT6.1) metastatic models. Results: The distribution patterns of 14C-fluciclovine, 3H-FDG, and 3H-choline, but not 99mTc-HMDP, were similar in both models, and the lesions where these tracers accumulated were, histologically, typical osteolytic and osteoblastic lesions. 99mTc-HMDP accumulated mostly in osteoblastic lesions. 14C-fluciclovine could visualize the osteolytic lesions as early as day 6 postinjection of MRMT-1. However, differential distributions in 14C-fluciclovine and 3H-FDG existed, based on histological differences: low 14C-fluciclovine and high 3H-FDG accumulation in osteolytic lesions with inflammation. In the osteoblastic metastatic model, visualization of osteoblastic lesions with 14C-fluciclovine was not clear, yet clearer than with 3H-FDG. Although half of the osteoblastic lesions with 14C-fluciclovine accumulation showed negligible 3H-choline accumulation in comparison, they were histologically similar to lesions with marked 14C-fluciclovine and 3H-choline accumulation. Conclusion: These results suggest that fluciclovine-PET can visualize true osteolytic and osteoblastic bone metastatic lesions.

Postnatal changes in skin water content in preterm infants.

BACKGROUND: Preterm infants have immature skin, which contributes to skin problems. Very little is known about postnatal changes in the skin, despite the clinical importance of this issue. AIM: To assess temporal changes in skin water content in preterm infants. STUDY DESIGN: A prospective observational study. SUBJECTS: Infants admitted to the neonatal intensive care unit were included in this study. OUTCOME MEASURES: Skin water content was measured at five different skin regions using dielectric methods at a depth of 1.5mm. Skin water content was measured on postnatal day 1 in 101 infants, and the correlation between skin water content and gestational week was analyzed. Measurements were also made on postnatal days 2, 3, and 7, and every 7days thereafter until the corrected age of 37weeks in 87 of the 101 infants. Temporal changes were statistically analyzed after dividing participants into seven groups by gestational age. RESULTS: On postnatal day 1, skin water content correlated inversely with gestational age at all skin regions. Skin water content decreased significantly over time, converging to the level of term infants by the corrected age of 32-35weeks. CONCLUSIONS: Skin water content at a depth of 1.5mm was related to corrected age and reached the level of term infants by the corrected age of approximately 32-35weeks.

Amino acid PET tracers are reliable markers of treatment responses to single-agent or combination therapies including temozolomide, interferon-ß, and/or bevacizumab for glioblastoma.

INTRODUCTION: We examined whether the amino acid PET tracers, trans-1-amino-3-(18)F-fluorocyclobutanecarboxylic acid (anti-(18)F-FACBC) and (11)C-methyl-l-methionine ((11)C-Met), are suitable for detecting early responses to combination therapies including temozolomide (TMZ), interferon-ß (IFN), and bevacizumab (Bev) in glioblastoma. METHODS: Human glioblastoma U87MG (U87) cells were incubated with low dose TMZ to induce chemoresistance. Both trans-1-amino-3-fluoro-1-(14)C-cyclobutanecarboxylic acid (anti-(14)C-FACBC) and (3)H-methyl-l-methionine ((3)H-Met) uptake were quantified using triple-label accumulation assays to examine the relationship between tracer uptake and proliferation ((3)H-thymidine (TdR) accumulation) in vitro. U87 and U87R (TMZ-resistant subculture) cells were inoculated into the right and left basal ganglia, respectively, of F344/N-rnu rats. The efficacy of single-agent (TMZ, Bev) and combination therapy (TMZ/IFN, TMZ/Bev, TMZ/IFN/Bev) was examined in orthotopic gliomas using MRI, Evans blue extravasation, anti-(14)C-FACBC, and (3)H-Met autoradiography, and MIB-1 immunostaining. RESULTS: TMZ treatment decreased (3)H-TdR accumulation and the volume distribution of anti-(14)C-FACBC and (3)H-Met in U87 but not U87R cells. TMZ/IFN combination therapy significantly decreased these parameters in U87R cells; however, Bev had no additional effect in vitro. In vivo, U87R-derived gliomas were observed as equivocal tumors on MRI and T2-high intensity lesions. Bev treatment, either alone or in combination, markedly decreased U87 enhancing lesions. By contrast, autoradiographic images using anti-(14)C-FACBC and (3)H-Met clearly delineated tumor extent, which spread widely beyond T2-high intensity lesions and enhancing lesions. TMZ therapy significantly decreased tracer accumulation and proliferation of U87- but not U87R-derived tumors. TMZ/IFN combination treatment significantly decreased these parameters in U87R tumors, which were further reduced (in both tumor types) by Bev addition. Tracer uptake correlated with the MIB-1 proliferation index. However, MRI was unsuitable for tumor delineation and assessment of Bev treatment response. CONCLUSIONS: Triple-agent therapy (TMZ/IFN/Bev) was effective against even TMZ-resistant glioblastomas. PET with amino acid tracers provides useful information on the early response of glioblastomas to single-agent and combination therapy.

[(14)C]Fluciclovine (alias anti-[(14)C]FACBC) uptake and ASCT2 expression in castration-resistant prostate cancer cells.

INTRODUCTION: trans-1-Amino-3-[(18)F]fluorocyclobutanecarboxylic acid ([(18)F]fluciclovine, also known as anti-[(18)F]FACBC), is a tracer for positron emission tomography (PET) imaging for detection of tumors such as prostate cancer (PCa). Our previous study showed that ASCT2 (Na(+)-dependent amino acid transporter (AAT)) mediates fluciclovine uptake in androgen-dependent PCa cells; its expression is influenced by androgen, a key hormone in the progression of primary PCa and castration-resistant prostate cancer (CRPC). In this study, we investigated the uptake mechanisms and feasibility of [(18)F]fluciclovine for CRPC in the androgen-dependent PCa cell line LNCaP and LNCaP-derivatives LNCaP-SF and LN-REC4. METHODS: LNCaP-SF was established after long-term cultivation of LNCaP in steroid-free conditions, and LN-Pre and LN-REC4 were established from LNCaP inoculated in intact and castrated severe combined immunodeficient mice, respectively. Uptake and competitive inhibition experiments were performed with trans-1-amino-3-fluoro[1-(14)C]cyclobutanecarboxylic acid ([(14)C]fluciclovine) to characterize the involvement of AATs in androgen-dependent PCa (LNCaP and LN-Pre) and CRPC-like (LNCaP-SF and LN-REC4) cell lines. AAT expression was analyzed by Western blotting, and [(14)C]fluciclovine uptake in androgen-dependent PCa and CRPC-like cell lines were investigated in the presence or absence of dihydrotestosterone (DHT). RESULTS: The contribution of Na(+)-dependent AATs to [(14)C]fluciclovine uptake in all cell lines was 88-98%, and [(14)C]fluciclovine uptake was strongly inhibited by L-glutamine and L-serine, the substrates for Na(+)-dependent alanine-serine-cysteine (system ASC) AATs, in the presence of Na(+). DHT enhanced ASCT2 expression in LNCaP, LN-Pre, and LN-REC4, but not in LNCaP-SF, and the responses of ASCT2 expression to DHT correlated with [(14)C]fluciclovine uptake. CONCLUSIONS: System ASC, especially ASCT2, could play a major role in [(14)C]fluciclovine uptake into CRPC-like and androgen-dependent PCa cells, suggesting [(18)F]fluciclovine-PET is applicable to the detection of CRPC as well as androgen-dependent PCa. ADVANCE IN KNOWLEDGE: [(18)F]fluciclovine-PET may be applied for the detection of CRPC. IMPLICATION FOR PATIENT CARE: [(18)F]fluciclovine-PET may permit early intervention for CRPC treatment.

Evaluation of trans-1-amino-3-18F-fluorocyclobutanecarboxylic acid accumulation in low-grade glioma in chemically induced rat models: PET and autoradiography compared with morphological images and histopathological findings.

INTRODUCTION: Magnetic resonance imaging (MRI) can have a problem to delineate diffuse gliomas with an intact blood-brain barrier (BBB) especially when a marked peritumoral edema is present. We evaluated the potential of trans-1-amino-3-(18)F-fluorocyclobutanecarboxylic acid (anti-(18)F-FACBC) positron emission tomography (PET) to delineate the extent of diffuse gliomas by comparing PET findings with autoradiography, in vivo and ex vivo MRI, and histopathology findings. METHODS: Dynamic PET was performed in rats with N-ethyl-N-nitrosourea-induced glioma for 60 min after anti-(18)F-FACBC injection. Contrast-enhanced MRI was performed before or after PET. The PET images were fused with in vivo and ex vivo MR images, and histopathological images for direct comparisons. Autoradiograms were compared with the results of Evans Blue (EB) extravasation (to assess BBB integrity) and hematoxylin-eosin staining. RESULTS: Histopathological examination, including EB extravasation assessment, and enhanced T1-weighted MRI identified several diffuse gliomas with slight BBB disruption, similar to low-grade human gliomas. Anti-(18)F-FACBC uptake was specific and high in the gliomas, irrespective of BBB integrity. Higher anti-(18)F-FACBC uptake corresponded to areas of T2 hyperintensity, independent of gadolinium enhancement. Ex vivo autoradiography also showed high anti-(18)F-FACBC accumulation in tumors lacking EB extravasation and a correlation between anti-(18)F-FACBC accumulation and tumor cell density, but not EB extravasation. CONCLUSIONS: Anti-(18)F-FACBC-PET allowed visualization of gliomas irrespective of BBB integrity. The tumor-to-normal uptake ratio of anti-(18)F-FACBC generally correlated with the relative cell density. Anti-(18)F-FACBC PET combined with MRI shows promise for preoperative glioma delineation. ADVANCES IN KNOWLEDGE: Radiopharmaceuticals that cross the BBB, such as anti-(18)F-FACBC, are taken up by low-grade gliomas with equivocal MRI findings due to an intact BBB. IMPLICATIONS FOR PATIENT CARE: Surgery is the first-line therapy for low-grade gliomas; therefore, delineation of their extent in the presence of an intact BBB is essential to planning surgery that removes the entire neoplasm, which will positively affect long-term survival.

Differences in transport mechanisms of trans-1-amino-3-[18F]fluorocyclobutanecarboxylic acid in inflammation, prostate cancer, and glioma cells: comparison with L-[methyl-11C]methionine and 2-deoxy-2-[18F]fluoro-D-glucose.

PURPOSE: We aimed to elucidate trans-1-amino-3-[(18)F]fluorocyclobutanecarboxylic acid (anti-[(18)F]FACBC) uptake mechanisms in inflammatory and tumor cells, in comparison with those of L-[methyl-(11)C]methionine ([(11)C]Met) and 2-deoxy-2-[(18)F]fluoro-D-glucose ([(18)F]FDG). PROCEDURES: Using carbon-14-labeled tracers, in vitro time-course, pH dependence, and competitive inhibition uptake experiments were performed in rat inflammatory (T cells, B cells, granulocytes, macrophages), prostate cancer (MLLB2), and glioma (C6) cells. RESULTS: Anti-[(14)C]FACBC uptake ratios of T/B cells to tumor cells were comparable, while those of granulocytes/macrophages to tumor cells were lower than those for [(14)C]FDG. Over half of anti-[(14)C]FACBC uptake by T/B and tumor cells was mediated by Na(+)-dependent amino acid transporters (system ASC), whereas most [(14)C]Met transport in all cells was mediated by Na(+)-independent carriers (system L). CONCLUSIONS: The low anti-[(18)F]FACBC accumulation in granulocytes/macrophages may be advantageous in discriminating inflamed regions from tumors. The significant anti-[(18)F]FACBC uptake in T/B cells may cause false-positives in some cancer patients who undergo FACBC-positron emission tomography (PET).

Comparison of trans-1-amino-3-[18F]fluorocyclobutanecarboxylic acid (anti-[18F]FACBC) accumulation in lymph node prostate cancer metastasis and lymphadenitis in rats.

INTRODUCTION: Trans-1-amino-3-[(18)F]fluorocyclobutanecarboxylic acid (anti-[(18)F]FACBC) is a positron emission tomography (PET) tracer used to visualize prostate cancer (PCa). In this study, we investigated the differences in anti-[(18)F]FACBC accumulation between metastatic and inflamed lymph node (LN) lesions. METHODS: A PCa LN metastasis (PLM) model was developed by inoculating a rat PCa cell line, MAT-Ly-Lu-B2, into popliteal LNs of Copenhagen rats. Acute lymphadenitis (AL) was induced by injecting concanavalin A (Con A) into the hind footpad, and chronic lymphadenitis (CL) was induced by daily injection of Con A into the tissues surrounding the popliteal LNs for 2weeks. Main lesions of all animal models were established in lumbar and/or inguinal LNs. Biodistribution and dynamic PET imaging data were acquired after tracer injection. T2-weighted magnetic resonance (MR) images were registered with PET images. RESULTS: In the biodistribution study, the uptake ratios of PLM-to-lymphadenitis in lesional lumbar and inguinal LNs were 0.97-1.57 and 1.47-2.08 at 15 and 60min post-anti-[(18)F]FACBC injection respectively. In PET imaging, the lesional lumbar LNs of CL and PLM, but not of AL, were visualized on anti-[(18)F]FACBC-PET/MR fusion images without disturbance from radioactivity from urine, and　the rank order of anti-[(18)F]FACBC accumulation at 50-60 post-injection in lesional lumbar LNs was PLM>CL>AL. CONCLUSIONS: Anti-[(18)F]FACBC accumulation in LNs with PLM was higher than that in inflamed LNs. ADVANCES IN KNOWLEDGE: The study showed that although low but significant levels of anti-[(18)F]FACBC uptake by chronic inflamed lesions might cause false-positives in anti-[(18)F]FACBC-PET in some PCa patients, uptake of the tracer at acutely inflamed sites was minimal. IMPLICATIONS FOR PATIENT CARE: The findings of this study suggest the potential of Anti-[(18)F]FACBC for distinguishing between tumors and acute inflammation in clinical practice.