Fructooligosaccharides Intake during Pregnancy Improves Metabolic Phenotype of Offspring in High Fat Diet-Induced Obese Mice.

SCOPE: Obesity and metabolic diseases are closely associated, and individuals who become obese are also prone to type 2 diabetes and cardiovascular disorders. Gut microbiota is mediated by diet and can influence host metabolism and the incidence of metabolic disorders. Recent studies have suggested that improving gut microbiota through a fructooligosaccharide (FOS)-supplemented diet may ameliorate obesity and other metabolic disorders. Although accumulating evidence supports the notion of the developmental origins of health and disease, the underlying mechanisms remain obscure. METHODS AND RESULTS: ICR mice are fed AIN-93G formula-based cellulose -, FOS-, acetate-, or propionate-supplemented diets during pregnancy. Offspring are reared by conventional ICR foster mothers for 4 weeks; weaned mice are fed high fat diet for 12 weeks and housed individually. The FOS and propionate offspring contribute to suppressing obesity and improving glucose intolerance. Gut microbial compositions in FOS-fed mothers and their offspring are markedly changed. However, the beneficial effect of FOS diet on the offspring is abolished when antibiotics are administered to pregnant mice. CONCLUSION: The findings highlight the link between the maternal gut environment and the developmental origin of metabolic syndrome in offspring. These results open novel research avenues into preemptive therapies for metabolic disorders by targeting the maternal gut microbiota.

Ring Growth Mechanism in the Reaction between Fulvenallenyl and Cyclopentadienyl Radicals.

Recombination between resonance-stabilized hydrocarbon radicals is an important class of reactions that contribute to molecular growth chemistry in combustion. In the present study, the ring growth mechanism in the reaction between fulvenallenyl (C7H5) and cyclopentadienyl (C5H5) radicals is investigated computationally. The reaction pathways are explored by quantum chemical calculations, and the phenomenological and steady-state rate constants are determined by solving the multiple-well master equations. The primary reaction routes following the recombination between the two radicals are found to be as follows: formation of the adducts, isomerization by hydrogen shift reactions, cyclization to form tricyclic compounds, and their isomerization and dissociation reactions, leading to the formation of acenaphthylene. The overall process can be approximately represented as C7H5 + C5H5 → acenaphthylene + 2H with the bimolecular rate constant of about 4 × 10-12 cm3 molecule-1 s-1. A reaction mechanism consisting of 20 reactions, including the formation, isomerization, and dissociation processes of major intermediate species, is proposed for use in kinetic modeling.

Generation of chimpanzee induced pluripotent stem cell lines for cross-species comparisons.

As humans' closest living relatives, chimpanzees offer valuable insights into human evolution. However, technical and ethical limitations hinder investigations into the molecular and cellular foundations that distinguish chimpanzee and human traits. Recently, induced pluripotent stem cells (iPSCs) have emerged as a novel model for functional comparative studies and provided a non-invasive alternative for studying embryonic phenomena. In this study, we generated five new chimpanzee iPSC lines from peripheral blood cells and skin fibroblasts with SeV vectors carrying four reprogramming factors (human OCT3/4, SOX2, KLF4, and L-MYC) and characterized their pluripotency and differentiation potential. We also examined the expression of a human-specific non-coding RNA, HSTR1, which is predicted to be involved in human brain development. Our results show that the chimpanzee iPSCs possess pluripotent characteristics and can differentiate into various cell lineages. Moreover, we found that HSTR1 is expressed in human iPSCs and their neural derivatives but not in chimpanzee counterparts, supporting its possible role in human-specific brain development. As iPSCs are inherently variable due to genetic and epigenetic differences in donor cells or reprogramming procedures, it is essential to expand the number of chimpanzee iPSC lines to comprehensively capture the molecular and cellular properties representative of chimpanzees. Hence, our cells provide a valuable resource for investigating the function and regulation of human-specific transcripts such as HSTR1 and for understanding human evolution more generally.

Differences in abductor hallucis activity during running in individuals with chronic ankle instability and copers.

BACKGROUND: Assessment of neuromuscular dysfunction following a lateral ankle sprain during running typically focuses on the activities of the extrinsic foot muscles. Although the interaction between intrinsic and extrinsic foot muscles has been reported, there are no studies on the activities of intrinsic foot muscles in individuals with chronic ankle instability and ankle sprain copers. RESEARCH QUESTION: Do copers and individuals with chronic ankle instability (CAI) have different abductor hallucis activity? METHODS: This study included 11 controls, 11 copers, and 16 CAI participants. A wireless surface electromyography system was applied to the abductor hallucis, peroneus longus, tibialis anterior, and medial gastrocnemius muscles. Running was performed on a treadmill (speed of 3.5 m/s). The stance phase is divided into four functional phases. The muscle activities during these phases were calculated using the root mean square standardized by the root mean square during static standing with a double-leg stance. RESULTS: Abductor hallucis activity was significantly lower during most phases in the coper and control groups than in the CAI group (P < 0.05). There were no differences in the extrinsic foot muscles among the groups (P > 0.05). SIGNIFICANCE: Simultaneous investigations of muscle activity in the abductor hallucis and extrinsic foot muscles identified neuromuscular dysfunction after ankle sprains. Increased activity of the abductor hallucis may be associated with recurrent ankle sprains.

Marsupials have monoallelic MEST expression with a conserved antisense lncRNA but MEST is not imprinted.

The imprinted isoform of the Mest gene in mice is involved in key mammalian traits such as placental and fetal growth, maternal care and mammary gland maturation. The imprinted isoform has a distinct differentially methylated region (DMR) at its promoter in eutherian mammals but in marsupials, there are no differentially methylated CpG islands between the parental alleles. Here, we examined similarities and differences in the MEST gene locus across mammals using a marsupial, the tammar wallaby, a monotreme, the platypus, and a eutherian, the mouse, to investigate how imprinting of this gene evolved in mammals. By confirming the presence of the short isoform in all mammalian groups (which is imprinted in eutherians), this study suggests that an alternative promoter for the short isoform evolved at the MEST gene locus in the common ancestor of mammals. In the tammar, the short isoform of MEST shared the putative promoter CpG island with an antisense lncRNA previously identified in humans and an isoform of a neighbouring gene CEP41. The antisense lncRNA was expressed in tammar sperm, as seen in humans. This suggested that the conserved lncRNA might be important in the establishment of MEST imprinting in therian mammals, but it was not imprinted in the tammar. In contrast to previous studies, this study shows that MEST is not imprinted in marsupials. MEST imprinting in eutherians, therefore must have occurred after the marsupial-eutherian split with the acquisition of a key epigenetic imprinting control region, the differentially methylated CpG islands between the parental alleles.

Initial evaluation of accelerator-based neutron source system at the Shonan Kamakura General Hospital.

An accelerator-based boron neutron capture therapy (AB-BNCT) system was installed at the Shonan Kamakura General Hospital (SKGH). We confirmed that a stable operation was possible for 1 h at a current of 30 mA. The evaluated thermal neutron flux was 2.8 × 109 cm-2 s-1 and in good agreement (±5%) with the calculated values. The daily variation was within ±2%. The ambient dose rate due to residual radioactivity after irradiation was approximately 5 µSv/h using a lead shutter.

Center of Pressure Deviation during Posture Transition in Athletes with Chronic Ankle Instability.

Center of pressure (COP) tracking during posture transition is an ideal scale for determining the recurrence of an ankle injury, thereby preventing chronic ankle instability (CAI). However, the same is difficult to determine because the reduced ability of certain patients (who experienced sprain) to control posture at the ankle joint is masked by the chain of hip and ankle joint motion. Thus, we observed the effects of knee joint immobilization/non-immobilization on postural control strategies during the posture transition task and attempted to evaluate the detailed pathophysiology of CAI. Ten athletes with unilateral CAI were selected. To examine differences in COP trajectories in the CAI side and non-CAI legs, patients stood on both legs for 10 s and one leg for 20 s with/without knee braces. COP acceleration during the transition was significantly higher in the CAI group with a knee brace. The COP transition from the double- to single-leg stance phase was significantly longer in the CAI foot. In the CAI group, the fixation of the knee joint increased COP acceleration during postural deviation. This suggests that there is likely an ankle joint dysfunction in the CAI group that is masked by the hip strategy.

Relative Biological Effectiveness Values of Spot-scanning Proton Beam Therapy at Shonan Kamakura General Hospital.

BACKGROUND/AIM: This study aimed to confirm the relative biological effectiveness (RBE) values of the proton beam therapy (PBT) system installed in Shonan Kamakura General Hospital. MATERIALS AND METHODS: Clonogenic cell-survival assays were performed with a human salivary gland (HSG) cell line, a human tongue squamous-cell carcinoma cell line (SAS), and a human osteosarcoma cell line (MG-63). Cells were irradiated with proton beams and X-rays with different doses (1.8, 3.6, 5.5, and 7.3 Gy for proton beams, and 2, 4, 6, and 8 Gy for X-rays). Proton beam irradiation used spot-scanning methods and three different depths (at the proximal, center, and distal sides of the spread-out Bragg peak). RBE values were obtained from a comparison of the dose that resulted in a surviving fraction of 10% (D10). RESULTS: D10 of proton beams at the proximal, center, and distal sides and X-rays in HSG were 4.71, 4.71, 4.51, and 5.25 Gy, respectively; those in SAS were 5.08, 5.04, 5.01, and 5.59 Gy, respectively; and those in MG-63 were 5.36, 5.42, 5.12, and 6.06 Gy, respectively. The RBE10 values at the proximal, center, and distal sides in HSG were 1.11, 1.11, and 1.16 respectively; those in SAS were 1.10, 1.11, and 1.12, respectively; and those in MG-63 were 1.13, 1.12, and 1.18, respectively. CONCLUSION: RBE10 values of 1.10-1.18 were confirmed by in vitro experiments using the PBT system. These results are considered acceptable for clinical use in terms of therapeutic efficacy and safety.

All-in-One Nanowire Assay System for Capture and Analysis of Extracellular Vesicles from an ex Vivo Brain Tumor Model.

Extracellular vesicles (EVs) have promising potential as biomarkers for early cancer diagnosis. The EVs have been widely studied as biological cargo containing essential biological information not only from inside vesicles such as nucleic acids and proteins but also from outside vesicles such as membrane proteins and glycolipids. Although various methods have been developed to isolate EVs with high yields such as captures based on density, size, and immunoaffinity, different measurement systems are needed to analyze EVs after isolation, and a platform that enables all-in-one analysis of EVs from capture to detection in multiple samples is desired. Since a nanowire-based approach has shown an effective capability for capturing EVs via surface charge interaction compared to other conventional methods, here, we upgraded the conventional well plate assay to an all-in-one nanowire-integrated well plate assay system (i.e., a nanowire assay system) that enables charge-based EV capture and EV analysis of membrane proteins. We applied the nanowire assay system to analyze EVs from brain tumor organoids in which tumor environments, including vascular formations, were reconstructed, and we found that the membrane protein expression ratio of CD31/CD63 was 1.42-fold higher in the tumor organoid-derived EVs with a p-value less than 0.05. Furthermore, this ratio for urine samples from glioblastoma patients was 2.25-fold higher than that from noncancer subjects with a p-value less than 0.05 as well. Our results demonstrated that the conventional well plate method integrated with the nanowire-based EV capture approach allows users not only to capture EVs effectively but also to analyze them in one assay system. We anticipate that the all-in-one nanowire assay system will be a powerful tool for elucidating EV-mediated tumor-microenvironment crosstalk.

Effectiveness of robust optimization against geometric uncertainties in TomoHelical planning for prostate cancer.

BACKGROUND: Geometrical uncertainties in patients can severely affect the quality of radiotherapy. PURPOSE: We evaluated the dosimetric efficacy of robust optimization for helical intensity-modulated radiotherapy (IMRT) planning in the presence of patient setup uncertainty and anatomical changes. METHODS: Two helical IMRT plans for 10 patients with localized prostate cancer were created using either minimax robust optimization (robust plan) or a conventional planning target volume (PTV) margin approach (PTV plan). Plan robustness was evaluated by creating perturbed dose plans with setup uncertainty from isocenter shifts and anatomical changes due to organ variation. The magnitudes of the geometrical uncertainties were based on the patient setup uncertainty considered during robust optimization, which was identical to the PTV margin. The homogeneity index, and target coverage (TC, defined as the V100% of the clinical target volume), and organs at risk (OAR; rectum and bladder) doses were analyzed for all nominal and perturbed plans. A statistical t-test was performed to evaluate the differences between the robust and PTV plans. RESULTS: Comparison of the nominal plans showed that the robust plans had lower OAR doses and a worse homogeneity index and TC than the PTV plans. The evaluations of robustness that considered setup errors more than the PTV margin demonstrated that the worst-case perturbed scenarios for robust plans had significantly higher TC while maintaining lower OAR doses. However, when anatomical changes were considered, improvement in TC from robust optimization was not observed in the worst-case perturbed plans. CONCLUSIONS: For helical IMRT planning in localized prostate cancer, robust optimization provides benefits over PTV margin-based planning, including better OAR sparing, and increased robustness against systematic patient-setup errors.

The Ventricular Hypokinesis at the Apical Pacing Site due to the Early Shortening and Rebound Stretch in a Case with Fontan Procedure.

The left ventricular (LV) apex is recommended as the first choice for positioning the epicardial pacing. We encountered a patient with congenital heart disease (CHD) showing hypokinesis of the LV apical pacing site after implantation of a pacemaker with epicardial leads. This phenomenon was revealed by the early shortening and systolic rebound stretch of the same lesion on two-dimensional speckle tracking echocardiography, which developed in the intraventricular dyssynchrony between the LV apex and base. Cardiac resynchronization therapy provided an excellent result around the hypokinetic lesion. It is wise to arrange detailed evaluations in each patient with complicated CHD, aiming at a successful treatment to enable ventricular synchronicity.

Placental imprinting of SLC22A3 in the IGF2R imprinted domain is conserved in therian mammals.

BACKGROUND: The eutherian IGF2R imprinted domain is regulated by an antisense long non-coding RNA, Airn, which is expressed from a differentially methylated region (DMR) in mice. Airn silences two neighbouring genes, Solute carrier family 22 member 2 (Slc22a2) and Slc22a3, to establish the Igf2r imprinted domain in the mouse placenta. Marsupials also have an antisense non-coding RNA, ALID, expressed from a DMR, although the exact function of ALID is currently unknown. The eutherian IGF2R DMR is located in intron 2, while the marsupial IGF2R DMR is located in intron 12, but it is not yet known whether the adjacent genes SLC22A2 and/or SLC22A3 are also imprinted in the marsupial lineage. In this study, the imprinting status of marsupial SLC22A2 and SLC22A3 in the IGF2R imprinted domain in the chorio-vitelline placenta was examined in a marsupial, the tammar wallaby. RESULTS: In the tammar placenta, SLC22A3 but not SLC22A2 was imprinted. Tammar SLC22A3 imprinting was evident in placental tissues but not in the other tissues examined in this study. A putative promoter of SLC22A3 lacked DNA methylation, suggesting that this gene is not directly silenced by a DMR on its promoter as seen in the mouse. Based on immunofluorescence, we confirmed that the tammar SLC22A3 is localised in the endodermal cell layer of the tammar placenta where nutrient trafficking occurs. CONCLUSIONS: Since SLC22A3 is imprinted in the tammar placenta, we conclude that this placental imprinting of SLC22A3 has been positively selected after the marsupial and eutherian split because of the differences in the DMR location. Since SLC22A3 is known to act as a transporter molecule for nutrient transfer in the eutherian placenta, we suggest it was strongly selected to control the balance between supply and demand of nutrients in marsupial as it does in eutherian placentas.

Evolution of the Short Form of DNMT3A, DNMT3A2, Occurred in the Common Ancestor of Mammals.

Genomic imprinting is found in marsupial and eutherian mammals, but not in monotremes. While the primary regulator of genomic imprinting in eutherians is differential DNA methylation between parental alleles, conserved imprinted genes in marsupials tend to lack DNA methylation at their promoters. DNA methylation at eutherian imprinted genes is mainly catalyzed by a DNA methyltransferase (DNMT) enzyme, DNMT3A. There are two isoforms of eutherian DNMT3A: DNMT3A and DNMT3A2. DNMT3A2 is the primary isoform for establishing DNA methylation at eutherian imprinted genes and is essential for eutherian genomic imprinting. In this study, we investigated whether DNMT3A2 is also present in the two other mammalian lineages, marsupials and monotremes. We identified DNMT3A2 in both marsupials and monotremes, although imprinting has not been identified in monotremes. By analyzing genomic sequences and transcriptome data across vertebrates, we concluded that the evolution of DNMT3A2 occurred in the common ancestor of mammals. In addition, DNMT3A/3A2 gene and protein expression during gametogenesis showed distinct sexual dimorphisms in a marsupial, the tammar wallaby, and this pattern coincided with the sex-specific DNA methylation reprogramming in this species as it does in mice. Our results show that DNMT3A2 is present in all mammalian groups and suggests that the basic DNMT3A/3A2-based DNA methylation mechanism is conserved at least in therian mammals.

Presence of H3K4me3 on Paternally Expressed Genes of the Paternal Genome From Sperm to Implantation.

Genomic imprinting, parent-of-origin-specific gene expression, is controlled by differential epigenetic status of the parental chromosomes. While DNA methylation and suppressive histone modifications established during gametogenesis suppress imprinted genes on the inactive allele, how and when the expressed allele gains its active status is not clear. In this study, we asked whether the active histone-3 lysine-4 trimethylation (H3K4me3) marks remain at paternally expressed genes (PEGs) in sperm and embryos before and after fertilization using published data. Here we show that mouse sperm had the active H3K4me3 at more than half of known PEGs, and these genes were present even after fertilization. Using reciprocal cross data, we identified 13 new transient PEGs during zygotic genome activation. Next, we confirmed that the 12 out of the 13 new transient PEGs were associated with the paternal H3K4me3 in sperm. Nine out of the 12 genes were associated with the paternal H3K4me3 in zygotes. Our results show that paternal H3K4me3 marks escape inactivation during the histone-to-protamine transition that occurs during sperm maturation and are present in embryos from early zygotic stages up to implantation.

Role of Neuroinflammation and Blood-Brain Barrier Permutability on Migraine.

Currently, migraine is treated mainly by targeting calcitonin gene-related peptides, although the efficacy of this method is limited and new treatment strategies are desired. Neuroinflammation has been implicated in the pathogenesis of migraine. In patients with migraine, peripheral levels of pro-inflammatory cytokines, such as interleukin-1ß (IL-1ß) and tumor necrosis factor-α, are known to be increased. Additionally, animal models of headache have demonstrated that immunological responses associated with cytokines are involved in the pathogenesis of migraine. Furthermore, these inflammatory mediators might alter the function of tight junctions in brain vascular endothelial cells in animal models, but not in human patients. Based on clinical findings showing elevated IL-1ß, and experimental findings involving IL-1ß and both the peripheral trigeminal ganglion and central trigeminal vascular pathways, regulation of the Il-1ß/IL-1 receptor type 1 axis might lead to new treatments for migraine. However, the integrity of the blood-brain barrier is not expected to be affected during attacks in patients with migraine.

Formation of polycyclic aromatic hydrocarbons, benzofuran, and dibenzofuran in fuel-rich oxidation of toluene using a flow reactor.

Recently, polycyclic aromatic hydrocarbons (PAHs) and oxygenated PAHs (OPAHs) have been attracting considerable attention owing to their high toxicity. Understanding their formation mechanism during combustion processes is important to control their emission. However, there are few studies that have quantitatively investigated OPAH formation in the fuel-rich oxidation of hydrocarbons, despite the availability of several studies on PAH formation. In this study, benzofuran and dibenzofuran as OPAHs were quantified in the fuel-rich oxidation of toluene using a flow reactor at atmospheric pressure in a temperature range of 1050-1350 K at equivalence ratios from 3.0 to 12.0 and residence times from 0.2 to 1.5 s. In addition to benzofuran and dibenzofuran, 4 types of monocyclic aromatic hydrocarbons and 19 types of PAHs were also evaluated. The experimental data obtained in this study were compared with those of the ethylene oxidation performed in our previous study. The existing kinetic model for PAH growth was modified based on several theoretical studies to predict the behavior of OPAHs with furan structures. The modified model showed significant improvements in the prediction of benzofuran and dibenzofuran formation. Based on the rate of production and sensitivity analysis using the modified model, the dominant reaction pathways of benzofuran and dibenzofuran were investigated.

Structure and Validity of Questionnaire for Oral Frail Screening.

Oral frailty is defined as the mild decline in oral function and located at the early and reversible stage of frailty. Therefore, early detection and early treatment of oral frailty is very useful. Simple and easy questionnaires, such as an oral frailty checklist, have been widely used for the screening and enlightenment of oral frailty of the Japanese people. We evaluate the structure and validity of the oral frailty checklist. The questionnaire of oral frailty was distributed for the citizens more than 50 years old from December 2018 to January 2019. The structural validity of the questionnaire is analyzed by structural equation modeling (SEM). The characteristics of the items are analyzed by Item Response Theory (IRT). The data of 725 subjects (360 men, 359 women, 6 no answer, mean age 71.3 ± 9.05) are analyzed. The questionnaire consisted of three latent variables. Items of "Brushing teeth at least twice a day", "Regular attendance of dental clinic", and "Using denture", had low discrimination ability. The questionnaire used in this study is a useful tool for the screening of oral frailty. However, its scoring system needs to be improved.

Does Last Year's Cost Predict the Present Cost? An Application of Machine Leaning for the Japanese Area-Basis Public Health Insurance Database.

The increasing healthcare cost imposes a large economic burden for the Japanese government. Predicting the healthcare cost may be a useful tool for policy making. A database of the area-basis public health insurance of one city was analyzed to predict the medical healthcare cost by the dental healthcare cost with a machine learning strategy. The 30,340 subjects who had continued registration of the area-basis public health insurance of Ebina city during April 2017 to September 2018 were analyzed. The sum of the healthcare cost was JPY 13,548,831,930. The per capita healthcare cost was JPY 446,567. The proportion of medical healthcare cost, medication cost, and dental healthcare cost was 78%, 15%, and 7%, respectively. By the results of the neural network model, the medical healthcare cost proportionally depended on the medical healthcare cost of the previous year. The dental healthcare cost of the previous year had a reducing effect on the medical healthcare cost. However, the effect was very small. Oral health may be a risk for chronic diseases. However, when evaluated by the healthcare cost, its effect was very small during the observation period.

Vitamin K2 Suppresses Proliferation and Inflammatory Cytokine Production in Mitogen-Activated Lymphocytes of Atopic Dermatitis Patients through the Inhibition of Mitogen-Activated Protein Kinases.

Vitamin K2 is suggested to have a suppressive effect on the peripheral blood mononuclear cells (PBMCs) of pediatric atopic dermatitis patients. We examined the molecular targets of vitamin K2 to suppress proliferation and cytokine production in T-cell mitogen-activated PBMCs of atopic dermatitis patients from the viewpoint of mitogen-activated protein kinase signaling molecules. The study population included 16 pediatric vitamin K2 patients and 21 healthy subjects. The effect of vitamin K2 on concanavalin A-activated PBMC proliferation was evaluated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and cell counting assays. T-helper (Th)1/Th2/Th17 cytokine profiles in plasma and PBMC-culture supernatants were analyzed by a cytometric beads array assay. Mitogen-activated protein kinase signaling molecules in concanavalin A-activated PBMCs were examined by enzyme-linked immunosorbent assay (ELISA) assays. At 10-100 µM, vitamin K2 significantly suppressed the proliferation of mitogen-activated PBMCs derived from atopic dermatitis patients and healthy subjects (p < 0.05). The interleukin (IL)-10 concentrations in plasma and the PBMC culture supernatants of atopic dermatitis patients were significantly higher than those of healthy subjects (p < 0.05). The IL-2 concentrations in the culture supernatants of atopic dermatitis PBMCs were significantly lower than those of healthy PBMCs (p < 0.05). Vitamin K2 significantly inhibited the IL-17A, IL-10, and tumor necrosis factor α (TNF-α) production (p < 0.05), and increased the IL-2 production (p < 0.01) in the culture supernatant of atopic dermatitis PBMCs. At 10-100 µM, vitamin K2 markedly decreased the of Mek1, extracellular signal-regulated kinases (ERK)1/2 mitogen-activated protein kinase, and SAPK/c-Jun N-terminal kinase (JNK) expression in atopic dermatitis PBMCs (p < 0.05). Vitamin K2 is suggested to attenuate activated T-cell immunity in atopic dermatitis patients through the inhibition of mitogen-activated protein kinase-Mek1-ERK1/2 and SAPK/JNK signaling pathways.

Impact of lifetime attributable risk of radiation-induced secondary cancer in proton craniospinal irradiation with vertebral-body-sparing for young pediatric patients with medulloblastoma.

We used the method proposed by Schneider et al. Theor Biol Med Model 2011;8:27, to clarify how the radiation-induced secondary cancer incidence rate changes in patients after proton craniospinal irradiation (CSI) without and with vertebral-body-sparing (VBS). Eight patients aged 3-15 years who underwent proton CSI were enrolled in the study. For each case, two types of plan without and with VBS in the target were compared. The prescribed doses were assumed to be 23.4 Gy relative biological effectiveness (RBE) and 36 Gy (RBE). Using the dose-volume histograms of the two plans, the lifetime attributable risk (LAR) was calculated by both methods for each patient based on the dose data calculated using an XiO-M treatment planning system. Eight organs were analyzed as follows: lung, colon, stomach, small intestine, liver, bladder, thyroid and bone. When the prescribed dose used was 23.4 Gy (RBE), the average LAR differences and the average number needed to treat (NNT) between proton CSI without and with VBS were 4.04 and 24.8, respectively, whereas the average LAR difference and the average NNT were larger at 8.65 and 11.6, respectively, when the prescribed dose of 36 Gy (RBE) was used. The LAR for radiation-induced secondary cancer was significantly lower in proton CSI with VBS than without VBS in pediatric patients, especially for the colon, lung, stomach and thyroid. The results of this study could serve as reference data when considering how much of vertebral bodies should be included when performing proton CSI according to age in clinical settings.