Integrated enhancer regulatory network by enhancer-promoter looping in gastric cancer.

Enhancer cis-regulatory elements play critical roles in gene regulation at many stages of cell growth. Enhancers in cancer cells also regulate the transcription of oncogenes. In this study, we performed a comprehensive analysis of long-range chromatin interactions, histone modifications, chromatin accessibility and expression in two gastric cancer (GC) cell lines compared to normal gastric epithelial cells. We found that GC-specific enhancers marked by histone modifications can activate a population of genes, including some oncogenes, by interacting with their proximal promoters. In addition, motif analysis of enhancer-promoter interacting enhancers showed that GC-specific transcription factors are enriched. Among them, we found that MYB is crucial for GC cell growth and activated by the enhancer with an enhancer-promoter loop and TCF7 upregulation. Clinical GC samples showed epigenetic activation of enhancers at the MYB locus and significant upregulation of TCF7 and MYB, regardless of molecular GC subtype and clinicopathological factors. Single-cell RNA sequencing of gastric mucosa with intestinal metaplasia showed high expression of TCF7 and MYB in intestinal stem cells. When we inactivated the loop-forming enhancer at the MYB locus using CRISPR interference (dCas9-KRAB), GC cell growth was significantly inhibited. In conclusion, we identified MYB as an oncogene activated by a loop-forming enhancer and contributing to GC cell growth.

Correction: Investigation of the new non-invasive semi-quantitative method of 123I-IMP pediatric cerebral perfusion SPECT.

[This corrects the article DOI: 10.1371/journal.pone.0241987.].

Two cases of strangulated bowel obstruction due to exposed vessel and nerve after laparoscopic and robot-assisted lateral lymph node dissection (LLND) for rectal cancer.

BACKGROUND: The majority of small bowel obstructions (SBO) are caused by adhesion due to abdominal surgery. Internal hernias, a very rare cause of SBO, can arise from exposed blood vessels and nerves during pelvic lymphadenectomy (PL). In this report, we present two cases of SBO following laparoscopic and robot-assisted lateral lymph node dissection (LLND) for rectal cancer, one case each, of which obstructions were attributed to the exposure of blood vessels and nerves during the procedures. CASE PRESENTATION: Case 1: A 68-year-old man underwent laparoscopic perineal rectal amputation and LLND for rectal cancer. Four years and three months after surgery, he visited to the emergency room with a chief complaint of left groin pain. Computed tomography (CT) revealed a closed-loop in the left pelvic cavity. We performed an open surgery to find that the small intestine was fitted into the gap between the left obturator nerve and the left pelvic wall, which was exposed by LLND. The intestine was not resected because coloration and peristalsis of the intestine improved after the hernia was released. The obturator nerve was preserved. Case 2: A 57-year-old man underwent a robot-assisted rectal amputation with LLND for rectal cancer. Eight months after surgery, he presented to the emergency room with a complaint of abdominal pain. CT revealed a closed-loop in the right pelvic cavity, and he underwent a laparoscopic surgery with a diagnosis of strangulated SBO. The small intestine was strangulated by an internal hernia caused by the right umbilical arterial cord, which was exposed by LLND. The incarcerated small intestine was released from the gap between the umbilical arterial cord and the pelvic wall. No bowel resection was performed. The umbilical arterial cord causing the internal hernia was resected. CONCLUSION: Although strangulated SBO due to an exposed intestinal cord after PL has been a rare condition to date, it is crucial for surgeons to keep this condition in mind.

SETD1A function in leukemia is mediated through interaction with mitotic regulators BuGZ/BUB3.

The H3K4 methyltransferase SETD1A plays a crucial role in leukemia cell survival through its noncatalytic FLOS domain-mediated recruitment of cyclin K and regulation of DNA damage response genes. In this study, we identify a functional nuclear localization signal in and interaction partners of the FLOS domain. Our screen for FLOS domain-binding partners reveals that the SETD1A FLOS domain binds mitosis-associated proteins BuGZ/BUB3. Inhibition of both cyclin K and BuGZ/BUB3-binding motifs in SETD1A shows synergistic antileukemic effects. BuGZ/BUB3 localize to SETD1A-bound promoter-TSS regions and SETD1A-negative H3K4me1-positive enhancer regions adjacent to SETD1A target genes. The GLEBS motif and intrinsically disordered region of BuGZ are required for both SETD1A-binding and leukemia cell proliferation. Cell-cycle-specific SETD1A restoration assays indicate that SETD1A expression at the G1/S phase of the cell cycle promotes both the expression of DNA damage response genes and cell cycle progression in leukemia cells.

Determination of Arsenic Species in Edible Insects by LC-ICP-MS.

BACKGROUND: Edible insects may contain arsenic. Analysis of arsenic species is necessary in order to accurately assess arsenic exposure. OBJECTIVE: An analytical method was validated and used to determine and quantitate arsenic species in edible insects. METHODS: Arsenic species were extracted from edible insects by heating at 100°C in 0.3 mol/L nitric acid. The concentration of arsenic species was then determined by LC-inductively coupled plasma-mass spectrometry (LC-ICP-MS) using an octadecylsilane (ODS) column with a mobile phase containing an ion-pair reagent. RESULTS: The LOD (0.007-0.012 mg/kg), LOQ (0.021-0.038 mg/kg), repeatability (1.2-3.2%), intermediate precision (2.8-4.5%), and trueness (recoveries 97-102% based on spiked samples) of the proposed method were satisfactory for inorganic arsenic, dimethylarsinic acid (DMA), and arsenobetaine (AB) in edible insects. Total arsenic was detected in all samples obtained in Japan (Asian forest scorpion, diving beetles, giant water bug, grasshoppers, June beetles, mole crickets, male rhino beetle, female rhino beetle, sago worms, and silkworm pupae) and consisted of mostly inorganic arsenic. Beetles in particular showed relatively high levels. CONCLUSION: Arsenic content varies among edible insect species. Feed control is important, as arsenic concentrations in edible insects may be feed dependent. HIGHLIGHTS: Arsenic species in edible insects were analyzed by LC-ICP-MS using an ODS column with a mobile phase containing an ion-pair reagent. Inorganic arsenic was detected in most samples, with concentrations ranging from <0.04 to 29.3 mg/kg.

Effect of Cholesterol Content of Lipid Composition in mRNA-LNPs on the Protein Expression in the Injected Site and Liver After Local Administration in Mice.

Delivery of messenger RNA (mRNA) using lipid nanoparticles (LNPs) is expected to be applied to various diseases following the successful clinical use of the mRNA COVID-19 vaccines. This study aimed to evaluate the effect of the cholesterol molar percentage of mRNA-LNPs on protein expression in hepatocellular carcinoma-derived cells and in the liver after intramuscular or subcutaneous administration of mRNA-LNPs in mice. For mRNA-LNPs with cholesterol molar percentages reduced to 10 mol% and 20 mol%, we formulated neutral charge particles with a diameter of approximately 100 nm and polydispersity index (PDI) <0.25. After the intramuscular or subcutaneous administration of mRNA-LNPs with different cholesterol molar percentages in mice, protein expression in the liver decreased as the cholesterol molar percentage in mRNA-LNPs decreased from 40 mol% to 20 mol% and 10 mol%, suggesting that reducing the cholesterol molar percentage in mRNA-LNPs decreases protein expression in the liver. Furthermore, in HepG2 cells, protein expression decreased as cholesterol in mRNA-LNPs was reduced by 40 mol%, 20 mol%, and 10 mol%. These results suggest that the downregulated expression of mRNA-LNPs with low cholesterol content in the liver involves degradation in systemic circulating blood and decreased protein expression after hepatocyte distribution.

Development of an apolipoprotein E mimetic peptide-lipid conjugate for efficient brain delivery of liposomes.

Liposomes are versatile carriers that can encapsulate various drugs; however, for delivery to the brain, they must be modified with a targeting ligand or other modifications to provide blood-brain barrier (BBB) permeability, while avoiding rapid clearance by reticuloendothelial systems through polyethylene glycol (PEG) modification. BBB-penetrating peptides act as brain-targeting ligands. In this study, to achieve efficient brain delivery of liposomes, we screened the functionality of eight BBB-penetrating peptides reported previously, based on high-throughput quantitative evaluation methods with in vitro BBB permeability evaluation system using Transwell, in situ brain perfusion system, and others. For apolipoprotein E mimetic tandem dimer peptide (ApoEdp), which showed the best brain-targeting and BBB permeability in the comparative evaluation of eight peptides, its lipid conjugate with serine-glycine (SG)5 spacer (ApoEdp-SG-lipid) was newly synthesized and ApoEdp-modified PEGylated liposomes were prepared. ApoEdp-modified PEGylated liposomes were effectively associated with human brain capillary endothelial cells via the ApoEdp sequence and permeated the membrane in an in vitro BBB model. Moreover, ApoEdp-modified PEGylated liposomes accumulated in the brain 3.9-fold higher than PEGylated liposomes in mice. In addition, the ability of ApoEdp-modified PEGylated liposomes to localize beyond the BBB into the brain parenchyma in mice was demonstrated via three-dimensional imaging with tissue clearing. These results suggest that ApoEdp-SG-lipid modification is an effective approach for endowing PEGylated liposomes with the brain-targeting ability and BBB permeability.

Stability Study of mRNA-Lipid Nanoparticles Exposed to Various Conditions Based on the Evaluation between Physicochemical Properties and Their Relation with Protein Expression Ability.

Lipid nanoparticles (LNPs) are currently in the spotlight as delivery systems for mRNA therapeutics and have been used in the Pfizer/BioNTech and Moderna COVID-19 vaccines. mRNA-LNP formulations have been indicated to require strict control, including maintenance at fairly low temperatures during their transport and storage. Since it is a new pharmaceutical modality, there is a lack of information on the systematic investigation of how storage and handling conditions affect the physicochemical properties of mRNA-LNPs and their protein expression ability. In this study, using the mRNA-LNPs with standard composition, we evaluated the effects of temperature, cryoprotectants, vibration, light exposure, and syringe aspiration from the vials on the physicochemical properties of nanoparticles in relation to their in vitro/in vivo protein expression ability. Among these factors, storage at -80 °C without a cryoprotectant caused a decrease in protein expression, which may be attributed to particle aggregation. Exposure to vibration and light also caused similar changes under certain conditions. Exposure to these factors can occur during laboratory and hospital handling. It is essential to have sufficient knowledge of the stability of mRNA-LNPs in terms of their physical properties and protein expression ability at an early stage to ensure reproducible research and development and medical care.

In vitro antibacterial activity of OPS-2071 against Gram-positive and Gram-negative enteropathogenic bacteria.

BACKGROUND: Enteric infections are a major public health issue in developing countries. Antimicrobial resistance is also a problem for enteric infection. OPS-2071 is a novel quinolone antibiotic with low oral absorption and potent antibacterial activity against Clostridioides difficile. OBJECTIVES: This study was conducted to confirm the antimicrobial activity of OPS-2071 against major enteropathogenic bacteria and to evaluate the risk of emergence of drug resistance. METHODS: The antibacterial activity was evaluated by the agar dilution method. The inhibitory activity against DNA gyrase and topoisomerase IV was determined by supercoiling assay and decatenation assay, respectively. The mutant prevention concentration and frequency of spontaneous resistance were determined by inoculation on drug-containing agar. RESULTS: Compared with the reference drugs, the antibacterial activity of OPS-2071 was more potent against Gram-positive bacteria and Campylobacter jejuni, including quinolone-resistant strains. Against other Gram-negative bacteria, OPS-2071 was comparable to existing quinolones. The inhibitory activities against DNA gyrase with quinolone-resistant mutations closely correlated with the antibacterial activity. Spontaneous resistance to OPS-2071 was not observed in Staphylococcus aureus and Escherichia coli and was lower than that of existing quinolones and higher than that of azithromycin in C. jejuni. The mutant prevention concentration of OPS-2071 was lower than that of tested compounds in S. aureus and C. jejuni and slightly higher than that of existing quinolones in E. coli. CONCLUSIONS: The broad and potent in vitro antibacterial activity and lower risk of drug resistance suggested that OPS-2071 may be useful for enteric infections caused by major pathogens including quinolone-resistant Campylobacter.

Antibacterial and Immunosuppressive Effects of OPS-2071, a Candidate Therapy for Inflammatory Bowel Disease.

BACKGROUND: Inflammatory bowel disease (IBD) is a chronic inflammatory disease of the gastrointestinal tract. Although many types of drug are used, clinical outcomes are still unsatisfactory. Previous studies have suggested that intestinal bacteria are involved in the pathogenesis of IBD. Accordingly, in an IBD model we evaluated the therapeutic effects of OPS-2071, a low-absorption quinolone antibacterial agent indicated for intestinal infection, and investigated its mechanism of action. METHODS: The therapeutic effects of OPS-2071 and comparison therapies were evaluated using naive CD4 + T cell-transfer IBD model mice. In vitro inhibition of LPS-induced TNF-α production and inhibitory effects on T cell responses stimulated using anti-CD3/CD28 antibody-loaded beads were evaluated using mouse splenocytes and human peripheral blood mononuclear cells. In addition, in vitro activities against bacteria implicated in IBD pathogenesis were tested. RESULTS: OPS-2071 dose-dependently decreased both colonic weight/length ratio and the colitis histological score as compared with the vehicle group. The therapeutic effect of OPS-2071 was equivalent to that of anti-IL-12/23 (p40) antibody. In vitro, OPS-2071 suppressed TNF-α production induced by LPS stimulation and T cell responses in a dose-dependent manner. At high concentrations, these effects were comparable to those of existing immunosuppressive agents, such as prednisolone, in both mouse and human cells. OPS-2071 also showed antibacterial activity against IBD-related bacteria. CONCLUSIONS: Our results suggest that OPS-2071 had both immunosuppressive and antibacterial effects. This dual effect makes OPS-2071 a unique and promising candidate for IBD.

[An Evaluation of Radiation Dose for Wide Volume Scan during Chest CT].

PURPOSE: A volume scan can cover a range of 160 mm with a single gantry rotation. It can be performed sequentially (a wide volume [WV] scan) to cover more than 160 mm, and volume Xact+ (Xact+) can be used when volume scan is done to extend the reconstruction area. The purpose of this study was to investigate the dose distribution and organ doses for a WV scan during chest CT. METHOD: We arranged radiophotoluminescence glass dosimeters (RPLDs) linearly on the surface and inside of the phantom to evaluate the dose distribution along the z-axis. We also placed RPLDs at the lens, thyroid, and breast positions to evaluate organ doses. We performed WV and helical scans and WV scan using Xact+. RESULT: The absorbed doses increased at the borders of the volume scans, and dose peaks were observed there. The organ doses for the WV scan outside the acquisition range were lower than those for the helical scan. The organ doses inside the acquisition range changed by the locations of borders. CONCLUSION: The WV scan increases the absorbed doses at the overlapping scanned regions, which can be reduced by using Xact+.

In Vitro and In Vivo Antibacterial Activities of a Novel Quinolone Compound, OPS-2071, against Clostridioides difficile.

OPS-2071 is a novel quinolone antibacterial agent characterized by low oral absorption that reduces the risk of adverse events typical of fluoroquinolone class antibiotics. The in vitro and in vivo antibacterial activities of OPS-2071 against Clostridioides difficile were evaluated in comparison to vancomycin and fidaxomicin. OPS-2071 exhibited potent antibacterial activity against 54 clinically isolated C. difficile strains with a MIC of 0.125 µg/ml (MIC50) and 0.5 µg/ml (MIC90), making it more active than vancomycin on a concentration basis (MIC50, 2 µg/ml; MIC90, 4 µg/ml) and comparable to fidaxomicin (MIC50, 0.063 µg/ml; MIC90, 8 µg/ml). OPS-2071 showed equally potent antibacterial activity against both hypervirulent and nonhypervirulent strains, while a significant difference in susceptibility to fidaxomicin was observed. Spontaneous resistance to OPS-2071 and vancomycin was not observed; however, resistance to fidaxomicin was observed at 4× MIC. The mutant prevention concentration of OPS-2071 was 16-fold lower than those of fidaxomicin and vancomycin, and the postantibiotic effect of OPS-2071 was longer than those of fidaxomicin and vancomycin. Also, OPS-2071 showed low systemic exposure, with OPS-2071 having 2.9% oral bioavailability at 1 mg/kg in rats. Furthermore, OPS-2071 showed significant in vivo efficacy at 0.0313 mg/kg/day (50% effective doses), 39.0-fold and 52.1-fold lower than those of vancomycin and fidaxomicin, respectively, in a hamster model of C. difficile infection. OPS-2071 has the potential to become a new therapeutic option for treating C. difficile infection.

Reversible cerebral vasoconstriction syndrome associated with tetrodotoxin poisoning: A case report.

An 81-year-old woman with a history of hypertension and Alzheimer's disease presented to the emergency department because of impaired consciousness. Physical examination revealed acute progressive generalized flaccid paralysis, hypertension, respiratory failure, and pupillary dilation. Although the patient did not complain of headache, head magnetic resonance angiography and magnetic resonance imaging showed multifocal segmental cerebral vasospasm and cerebral infarction in the left occipital lobe. Her family reported that although she did not have a license to cook pufferfish, she was in the habit of eating pufferfish. We subsequently detected tetrodotoxin in the patient's urine, and she was diagnosed with tetrodotoxin poisoning. As the symptoms of tetrodotoxin intoxication improved, head magnetic resonance angiography showed the disappearance of the multifocal segmental cerebral vasospasm. The patient's clinical course and imaging findings were consistent with reversible cerebral vasoconstriction syndrome (RCVS). Sympathetic overactivity after tetrodotoxin intoxication possibly caused the development of RCVS, and RCVS could not be ruled out even in the absence of the typical thunderclap headache. Magnetic resonance angiography is a useful modality when performing repeated examinations.

Investigation of the new non-invasive semi-quantitative method of 123I-IMP pediatric cerebral perfusion SPECT.

In pediatric cases requiring quantification of cerebral blood flow (CBF) using 123I-N-isopropyl-p-iodoamphetamine (123I-IMP) single-photon emission computed tomography (SPECT), arterial blood sampling is sometimes impossible due to issues such as movement, crying, or body motion. If arterial blood sampling fails, quantitative diagnostic assessment becomes impossible despite radiation exposure. We devised a new easy non-invasive microsphere (e-NIMS) method using whole-body scan data. This method can be used in conjunction with autoradiography (ARG) and can provide supportive data for invasive CBF quantification. In this study, we examined the usefulness of e-NIMS for pediatric cerebral perfusion semi-quantitative SPECT and compared it with the invasive ARG. The e-NIMS estimates cardiac output (CO) using whole-body acquisition data after 123I-IMP injection and the body surface area from calculation formula. A whole-body scan was performed 5 minutes after the 123I-IMP injection and CO was estimated by region of interest (ROI) counts measured for the whole body, lungs, and brain using the whole-body anterior image. The mean CBF (mCBF) was compared with that acquired via ARG in 115 pediatric patients with suspected cerebrovascular disorders (age 0-15 years). Although the mCBF estimated by the e-NIMS indicated a slight deviation in the extremely low- or high-mCBF cases when compared with the values acquired using the invasive ARG, there was a good correlation between the two methods (r = 0.799; p < 0.001). There were no significant differences in the mCBF values based on physical features, such as patients' height, weight, and age. Our findings suggest that 123I-IMP brain perfusion SPECT with e-NIMS is the simplest semi-quantitative method that can provide supportive data for invasive CBF quantification. This method may be useful, especially in pediatric brain perfusion SPECT, when blood sampling or identifying pulmonary arteries for CO estimation using the graph plot method is difficult.

Cumulative Fraction of Response for Once- and Twice-Daily Delamanid in Patients with Pulmonary Multidrug-Resistant Tuberculosis.

Pharmacokinetic (PK) and pharmacodynamic (PD) analyses were conducted to determine the cumulative fraction of response (CFR) for 100 mg twice-daily (BID) and 200 mg once-daily (QD) delamanid in patients with multidrug-resistant tuberculosis (MDR-TB), using a pharmacodynamic target (PDT) that achieves 80% of maximum efficacy. First, in the mouse model of chronic TB, the PK/PD index for delamanid efficacy was determined to be area under the drug concentration-time curve over 24 h divided by MIC (AUC0-24/MIC), with a PDT of 252. Second, in the hollow-fiber system model of tuberculosis, plasma-equivalent PDTs were identified as an AUC0-24/MIC of 195 in log-phase bacteria and 201 in pH 5.8 cultures. Third, delamanid plasma AUC0-24/MIC and sputum bacterial decline data from two early bactericidal activity trials identified a clinical PDT of AUC0-24/MIC of 171. Finally, the CFRs for the currently approved 100-mg BID dose were determined to be above 95% in two MDR-TB clinical trials. The CFR for the 200-mg QD dose, evaluated in a trial in which delamanid was administered as 100 mg BID for 8 weeks plus 200 mg QD for 18 weeks, was 89.3% based on the mouse PDT and >90% on the other PDTs. QTcF (QTc interval corrected for heart rate by Fridericia's formula) prolongation was approximately 50% lower for the 200 mg QD dose than the 100 mg BID dose. In conclusion, while CFRs of 100 mg BID and 200 mg QD delamanid were close to or above 90% in patients with MDR-TB, more-convenient once-daily dosing of delamanid is feasible and likely to have less effect on QTcF prolongation.

OPC-167832, a Novel Carbostyril Derivative with Potent Antituberculosis Activity as a DprE1 Inhibitor.

There is an urgent need for new, potent antituberculosis (anti-TB) drugs with novel mechanisms of action that can be included in new regimens to shorten the treatment period for TB. After screening a library of carbostyrils, we optimized 3,4-dihydrocarbostyril derivatives and identified OPC-167832 as having potent antituberculosis activity. The MICs of the compound for Mycobacterium tuberculosis ranged from 0.00024 to 0.002 µg/ml. It had bactericidal activity against both growing and intracellular bacilli, and the frequency of spontaneous resistance for M. tuberculosis H37Rv was less than 1.91 × 10-7 It did not show antagonistic effects with other anti-TB agents in an in vitro checkerboard assay. Whole-genome and targeted sequencing of isolates resistant to OPC-167832 identified decaprenylphosphoryl-ß-d-ribose 2'-oxidase (DprE1), an essential enzyme for cell wall biosynthesis, as the target of the compound, and further studies demonstrated inhibition of DprE1 enzymatic activity by OPC-167832. In a mouse model of chronic TB, OPC-167832 showed potent bactericidal activities starting at a dose of 0.625 mg/kg of body weight. Further, it exhibited significant combination effects in 2-drug combinations with delamanid, bedaquiline, or levofloxacin. Finally, 3- or 4-drug regimens comprised of delamanid and OPC-167832 as the core along with bedaquiline, moxifloxacin, or linezolid showed efficacy in reducing the bacterial burden and preventing relapse superior to that of the standard treatment regimen. In summary, these results suggest that OPC-167832 is a novel and potent anti-TB agent, and regimens containing OPC-167832 and new or repurposed anti-TB drugs may have the potential to shorten the duration of treatment for TB.

Adduct Formation of Delamanid with NAD in Mycobacteria.

Delamanid (DLM), a nitro-dihydroimidazooxazole derivative currently approved for pulmonary multidrug-resistant tuberculosis (TB) therapy, is a prodrug activated by mycobacterial 7,8-didemethyl-8-hydroxy 5-deazaflavin electron transfer coenzyme (F420)-dependent nitroreductase (Ddn). Despite inhibiting the biosynthesis of a subclass of mycolic acids, the active DLM metabolite remained unknown. Comparative liquid chromatography-mass spectrometry (LC-MS) analysis of DLM metabolites revealed covalent binding of reduced DLM with a nicotinamide ring of NAD derivatives (oxidized form) in DLM-treated Mycobacterium tuberculosis var. Bacille de Calmette et Guérin. Isoniazid-resistant mutations in the type II NADH dehydrogenase gene (ndh) showed a higher intracellular NADH/NAD ratio and cross-resistance to DLM, which were restored by complementation of the mutants with wild-type ndh Our data demonstrated for the first time the adduct formation of reduced DLM with NAD in mycobacterial cells and its importance in the action of DLM.

Diaryliodonium Salt-Mediated Intramolecular C-N Bond Formation Using Boron-Masking N-Hydroxyamides.

Intramolecular aromatic C-N bond formation reactions using electron-rich aromatic tethered boron-masking N-hydroxyamide as substrate were realized. These new C-N bond formation reactions involve the in situ generation of a diaryliodonium salt by treatment with hypervalent iodine, deborylation by base treatment, spontaneous N → O acyl migration, cyclization, reductive elimination, elimination of benzoic acid, and tautomerization to indole formation. Hereby, we obtained highly functionalized electron-rich indoles and quinoline in practical yields.

Investigation of the relation between administered dose and image quality for pediatric 99mTc-DMSA renal scintigraphy: clinical study applying the JSNM (Japanese Society of Nuclear Medicine) pediatric dosage card : The Japanese Society of Nuclear Medicine Technology (JSNMT), the Optimization of Imaging Technique Committee for Pediatric Nuclear Medicine Studies.

PURPOSE: In 2013, the Japanese Society of Nuclear Medicine (JSNM) announced consensus guidelines for pediatric nuclear medicine. These JSNM guidelines proposed use of lower administered doses compared with traditionally determined doses, which were estimated from age, weight or body surface area (BSA) based on the administered dose for adults in Japan. When the JSNM guidelines are used, the relationship between this recommended administered dose and image quality remains unclear. In this study, we clarified the relationship between administered dose and image quality for pediatric 99mTc-DMSA renal scan retrospectively, and verified the diagnosable image quality with the recommended administered dose of the JSNM guidelines. MATERIALS AND METHODS: Data from 7 pediatric patients who underwent 99mTc-DMSA dynamic renal scans according to the guidelines' recommended doses were collected. Scan frame rate was 1 frame/min, and scan time was up to 8 min. Eight images, which had different acquired time periods from 1 min to 8 min were prepared by adding each frame. Nine nuclear medicine specialists determined 8 images with different acquired times as diagnosable or undiagnosable. A region of interest (ROI) with 50% thresholds was placed on each kidney of every image. Coefficient of variation (CV) was calculated by dividing the standard deviation (σ) by the mean counts (µ) of each ROI (CV = σ/µ × 100). 99mTc-DMSA renal scans (total of 2821 cases) that were performed previously in collaboration with 6 hospitals were collected, and CVs of these images were calculated in all cases. These 2821 cases were separated into 5 groups for every 10 kg weight; i.e., (1) less than 10 kg, (2) 10-19.9 kg, (3) 20-29.9 kg, (4) 30-39.9 kg, and (5) above 40 kg. Regression line of each group was analyzed in relation to the CV and administered dose. The CV at the point of intersection with the recommended dose range from the guideline was determined for each group. This CV value was considered as the estimated CV of the image obtained when the recommended dose of the guideline was used. Thus, if the CV was equal to or less than the estimated CV value, then the diagnostic image quality was deemed satisfactory. RESULTS: Average CV of the lower limit of diagnosable images in 7 cases as determined by 9 nuclear medicine specialists was 19.9%. Estimated CV was 21.2-24.2% in the group weighing < 10 kg (group 1), 19.9-20.6% in the group weighing > 10 kg and < 20 kg (group 2), 19.6% in group weighing > 20 kg and < 30 kg (group 3), 19.4-19.5% in the group weighing > 30 kg and < 40 kg (group 4), and 19.8% in the group weighing > 40 kg (group 5). The estimated CVs from groups 1 and 2 with weight < 20 kg exceeded 19.9%. CONCLUSIONS: Although 99mTc-DMSA renal scan can be carried out using the guidelines' recommended dose with conventional image acquisition time in patients weighing 20 kg or more, those < 20 kg need consideration for a longer image acquisition time to obtain diagnosable images.