Inhalation of hydrogen gas mitigates sevoflurane-induced neuronal apoptosis in the neonatal cortex and is associated with changes in protein phosphorylation.

Inhalation of hydrogen (H2) gas is therapeutically effective for cerebrovascular diseases, neurodegenerative disorders, and neonatal brain disorders including pathologies induced by anesthetic gases. To understand the mechanisms underlying the protective effects of H2 on the brain, we investigated the molecular signals affected by H2 in sevoflurane-induced neuronal cell death. We confirmed that neural progenitor cells are susceptible to sevoflurane and undergo apoptosis in the retrosplenial cortex of neonatal mice. Co-administration of 1-8% H2 gas for 3 h to sevoflurane-exposed pups suppressed elevated caspase-3-mediated apoptotic cell death and concomitantly decreased c-Jun phosphorylation and activation of the c-Jun pathway, all of which are induced by oxidative stress. Anesthesia-induced increases in lipid peroxidation and oxidative DNA damage were alleviated by H2 inhalation. Phosphoproteome analysis revealed enriched clusters of differentially phosphorylated proteins in the sevoflurane-exposed neonatal brain that included proteins involved in neuronal development and synaptic signaling. H2 inhalation modified cellular transport pathways that depend on hyperphosphorylated proteins including microtubule-associated protein family. These modifications may be involved in the protective mechanisms of H2 against sevoflurane-induced neuronal cell death.

Long-Term Survival of a Patient With Anaplastic Thyroid Carcinoma Treated With Hypofractionated Radiotherapy: A Case Report.

Anaplastic thyroid carcinoma, a rare type of primary thyroid cancer, is one of the most aggressive neoplasms with a poor prognosis. Many cases are in the advanced stage at the time of the initial visit, and curative treatment is impossible. Because of the highly radioresistant nature of anaplastic thyroid carcinoma, this condition cannot be properly controlled with conventional radiotherapy. Herein, we report the case of a patient with anaplastic thyroid carcinoma who underwent hypofractionated radiotherapy, attained a complete response, and is still alive more than 10 years after treatment with no evidence of disease. To overcome the high radioresistance of anaplastic thyroid carcinoma, we administered 50 Gy in 10 fractions three times a week. Furthermore, we administered paclitaxel and carboplatin sequentially before and after radiotherapy. Consequently, the patient completed treatment and reached a complete response. He is still alive more than 10 years after treatment with no evidence of disease or severe adverse events. Hypofractionated radiation therapy may provide good control of locally advanced anaplastic thyroid carcinoma.

Investigation of the efficacy of the change ratio of brain natriuretic peptide for predicting the cardiac effects of chemoradiotherapy on esophageal cancer.

The aim of this study was to investigate the effectiveness of brain natriuretic peptide (BNP) as a predictor of radiological effects on the heart. A total of 41 patients with esophageal cancer who underwent chemoradiotherapy (CRT) were retrospectively investigated. The BNP levels were measured on the first day of CRT (pre-CRT) and the last day of CRT (post-CRT), and the median concentration of BNP and dosimetric parameters of the heart were calculated. The change ratio of BNP was calculated as follows: [(BNP post-CRT) - (BNP pre-CRT)]/(BNP pre-CRT). The comparison of BNP pre-CRT with post-CRT was performed using a Wilcoxon signed-rank test. The relationship between dosimetric parameters and change ratio was analyzed using Spearman's correlation coefficient. The median levels of BNP of pre-CRT and post-CRT were 10 and 22 pg/ml, respectively, and the difference was statistically significant (P<0.0001). Significant correlations (all P<0.05) were observed between the change ratio and mean dose, V5, V10, V20, and V30. Of the cohort, 14 patients developed acute-to-subacute cardiac events, such as pericardial effusion, cardiomegaly, acute exacerbation of chronic heart failure, and a decreased ejection fraction. The change ratios of BNP, V5, V10, V20, and V30 were significantly higher in patients who experienced cardiac events compared with those who did not. The results of this study showed that BNP measurement, particularly the change ratio of BNP pre- and post-CRT, may be a useful cardiac event predictor in addition to dosimetric parameters.

Effects of six-cycle completion and earlier use of radium-223 therapy on prognosis for metastatic castration-resistant prostate cancer: A real-world multicenter retrospective study.

OBJECTIVES: To evaluate the effect of 6-cycle completion and earlier use of radium-233 dichloride (Ra223) on the prognosis of patients with metastatic castration-resistant prostate cancer (mCRPC). METHODS: We retrospectively evaluated 75 patients with bone metastases-predominant mCRPC who were treated with Ra223 between August 2016 and August 2021. The primary purpose of the study was to assess the effect of Ra223 completion (6 cycles) on patient prognosis, and the secondary purpose was to investigate factors associated with Ra223 incompletion (fewer than 6 cycles) and overall survival. RESULTS: The median age of the patients was 72 years. The median number of Ra223 administrations was 6 (interquartile range, 5-6), and the median Ra223 completion rate was 75%. The median time from mCRPC diagnosis to Ra223 administration was 17 months, and the median number of prior treatments was 2. Multivariable analysis indicated that unfavorable performance status (>0), prostate-specific antigen (PSA) level >10 ng/ml, extension of bone metastasis score 3 to 4, and Ra223 incompletion were significantly associated with poor overall survival. In addition, EOD 3 to 4 and 3 or more prior CRPC treatments were significantly associated with Ra223 incompletion. CONCLUSION: Six-cycle completion and earlier administration of Ra233 are potentially associated with favorable survival. Unfavorable factors (EOD 3-4 and ≥3 prior treatments) were significantly associated with Ra223 incompletion.

Impact of low iodine density tumor area ratio on the local control of non-small cell lung cancer through stereotactic body radiotherapy.

Lung cancer with low average iodine density measured via contrast-enhanced computed tomography (CT) using dual-energy CT technology has shown a reduced local control rate after stereotactic body radiotherapy (SBRT). The current study therefore investigated the relationship between low iodine density tumor area and its ratio and local recurrence after SBRT. Dual-energy CT was performed on the day before SBRT initiation, with a low iodine density tumor area being defined as that with an iodine density of <1.81 mg cm-3. The low iodine density tumor area, the ratio between the low iodine density tumor area and the entire tumor, and the local recurrence rate were then determined. No correlation was observed between the low iodine density tumor area and the local recurrence rate. However, tumors with a large low iodine density tumor area ratio showed an increased local recurrence rate, with the prognostic accuracy almost similar to that in previous studies using average iodine densities. Our results therefore suggest that the low iodine density tumor area ratio was a useful prognostic index after SBRT, with an accuracy comparable with that of the average iodine density.

Automatic Redirection of Carbon Flux between Glycolysis and Pentose Phosphate Pathway Using an Oxygen-Responsive Metabolic Switch in Corynebacterium glutamicum.

Controlling the carbon flux into a desired pathway is important for improving product yield in metabolic engineering. After entering a cell, glucose is channeled into glycolysis and the pentose phosphate pathway (PPP), which decreases the yield of target products whose synthesis relies on NADPH as a cofactor. Here, we demonstrate redirection of carbon flux into PPP under aerobic conditions in Corynebacterium glutamicum, achieved by replacing the promoter of glucose 6-phosphate isomerase gene (pgi) with an anaerobic-specific promoter of the lactate dehydrogenase gene (ldhA). The promoter replacement increased the split ratio of carbon flux into PPP from 39 to 83% under aerobic conditions. The titer, yield, and production rate of 1,5-diaminopentane, whose synthesis requires NADPH as a cofactor, were increased by 4.6-, 4.4-, and 2.6-fold, respectively. This is the largest improvement in the production of 1,5-diaminopentane or its precursor, lysine, reported to date. After aerobic cell growth, pgi expression was automatically induced under anaerobic conditions, altering the carbon flux from PPP to glycolysis, to produce succinate in a single metabolically engineered strain. Such an automatic redirection of metabolic pathway using an oxygen-responsive switch enables two-stage fermentation for efficient production of two different compounds by a single strain, potentially reducing the production costs and time for practical applications.

Molecular hydrogen attenuates gefitinib-induced exacerbation of naphthalene-evoked acute lung injury through a reduction in oxidative stress and inflammation.

Although inhibition of epidermal growth factor receptor (EGFR)-mediated cell signaling by the EGFR tyrosine kinase inhibitor gefitinib is highly effective against advanced non-small cell lung cancer, this drug might promote severe acute interstitial pneumonia. We previously reported that molecular hydrogen (H2) acts as a therapeutic and preventive anti-oxidant. Here, we show that treatment with H2 effectively protects the lungs of mice from severe damage caused by oral administration of gefitinib after intraperitoneal injection of naphthalene, the toxicity of which is related to oxidative stress. Drinking H2-rich water ad libitum mitigated naphthalene/gefitinib-induced weight loss and significantly improved survival, which was associated with a decrease in lung inflammation and inflammatory cytokines in the bronchoalveolar lavage fluid. Naphthalene decreased glutathione in the lung, increased malondialdehyde in the plasma, and increased 4-hydroxy-2-nonenal production in airway cells, all of which were mitigated by H2-rich water, indicating that the H2-rich water reverses cellular damage to the bronchial wall caused by oxidative stress. Finally, treatment with H2 did not interfere with the anti-tumor effects of gefitinib on a lung cancer cell line in vitro or on tumor-bearing mice in vivo. These results indicate that H2-rich water has the potential to improve quality of life during gefitinib therapy by mitigating lung injury without impairing anti-tumor activity.

Administration of hydrogen-rich water prevents vascular aging of the aorta in LDL receptor-deficient mice.

The main cause of arteriosclerosis is atherosclerosis in the aorta. Atherosclerosis is recognized as a chronic inflammatory condition that begins with the dysfunction or activation of arterial endothelium. Low-density lipoprotein (LDL) and especially its oxidized form play a key role in endothelial dysfunction and atherogenesis. Recent studies showed that senescent cells are involved in the development and progression of atherosclerosis, and eliminating senescent cells suppresses the senescence-associated secretory phenotype. We previously reported that molecular hydrogen-rich water (HW) has antioxidant and anti-inflammatory effects in numerous diseases. Here, we used LDL receptor-deficient mice fed a high-fat diet (HFD) for 13 weeks as a model for atherosclerosis and evaluated the effects of continuous administration of HW. The numbers of endothelial cells in the atheroma expressing the senescence factors p16INK4a and p21 decreased in HFD-fed mice given HW compared with HFD-fed mice given control water. Furthermore, macrophage infiltration and Tnfα expression in the atheroma were also suppressed. These results suggest that vascular aging can be suppressed by HW.

The potential failure risk of the cone-beam computed tomography-based planning target volume margin definition for prostate image-guided radiotherapy based on a prospective single-institutional hybrid analysis.

BACKGROUND: The purpose of this study was to evaluate the impact of markerless on-board kilovoltage (kV) cone-beam computed tomography (CBCT)-based positioning uncertainty on determination of the planning target volume (PTV) margin by comparison with kV on-board imaging (OBI) with gold fiducial markers (FMs), and to validate a methodology for the evaluation of PTV margins for markerless kV-CBCT in prostate image-guided radiotherapy (IGRT). METHODS: A total of 1177 pre- and 1177 post-treatment kV-OBI and 1177 pre- and 206 post-treatment kV-CBCT images were analyzed in 25 patients who received prostate IGRT with daily localization by implanted FMs. Intrafractional motion of the prostate was evaluated between each pre- and post-treatment image with these two different techniques. The differences in prostate deviations and intrafractional motions between matching by FM in kV-OBI (OBI-FM) and matching by soft tissues in kV-CBCT (CBCT-ST) were compared by Bland-Altman limits of agreement. Compensated PTV margins were determined and compensated by references. RESULTS: Mean differences between OBI-FM and CBCT-ST in the anterior to posterior (AP), superior to inferior (SI), and left to right (LR) directions were - 0.43 ± 1.45, - 0.09 ± 1.65, and - 0.12 ± 0.80 mm, respectively, with R2 = 0.85, 0.88, and 0.83, respectively. Intrafractional motions obtained from CBCT-ST were 0.00 ± 1.46, 0.02 ± 1.49, and 0.15 ± 0.64 mm, respectively, which were smaller than the results from OBI-FM, with 0.43 ± 1.90, 0.12 ± 1.98, and 0.26 ± 0.80 mm, respectively, with R2 = 0.42, 0.33, and 0.16, respectively. Bland-Altman analysis showed a significant proportional bias. PTV margins of 1.5 mm, 1.4 mm, and 0.9 mm for CBCT-ST were calculated from the values of CBCT-ST, which were also smaller than the values of 3.15 mm, 3.66 mm, and 1.60 mm from OBI-FM. The practical PTV margin for CBCT-ST was compensated with the values from OBI-FM as 4.1 mm, 4.8 mm, and 2.2 mm. CONCLUSIONS: PTV margins calculated from CBCT-ST might be underestimated compared to the true PTV margins. To determine a reliable CBCT-ST-based PTV margin, at least the systemic error Σ and the random error σ for on-line matching errors need to be investigated by supportive preliminary FM evaluation at least once.

Skeletal muscle cell contraction reduces a novel myokine, chemokine (C-X-C motif) ligand 10 (CXCL10): potential roles in exercise-regulated angiogenesis.

Accumulating evidence indicates that skeletal muscle secrets proteins referred to as myokines and that exercise contributes to their regulation. In this study, we propose that chemokine (C-X-C motif) ligand 10 (CXCL10) functions as a novel myokine. Initially, we stimulated differentiated C2C12 myotubes with or without electrical pulse stimulation (EPS) to identify novel myokines. Cytokine array analysis revealed that CXCL10 secretion was significantly reduced by EPS, which was further confirmed by enzyme-linked immunosorbent assay and quantitative polymerase chain reaction analysis. Treadmill experiments in mice identified significant reduction of Cxcl10 gene expression in the soleus muscle. Additionally, contraction-dependent p38 MAPK activation appeared to be involved in this reduction. Furthermore, C2C12 conditioned medium obtained after applying EPS could induce survival of MSS31, a vascular endothelial cell model, which was partially attenuated by the addition of recombinant CXCL10. Overall, our findings suggest CXCL10 as a novel exercise-reducible myokine, to control endothelial cell viability.

Analysis of the relationship between prescribed dose and dosimetric advantage of real-time intraoperatively built custom-linked seeds in iodine-125 prostate brachytherapy.

BACKGROUND: The purpose of this study was to investigate the differences in the dosimetric advantage of using intraoperatively built custom-linked (IBCL) seeds between permanent iodine-125 (I-125) seed implantation (PI) alone and PI followed by external-beam radiation therapy (EBRT) for prostate cancer. METHODS: We reviewed the records of 62 patients with localized prostate cancer who received transperineal interstitial brachytherapy with I-125 using free seeds or IBCL seeds. Twenty-four low- and intermediate-risk patients underwent PI alone with the prescribed dose of 160 Gy, and 39 high-risk patients underwent PI with 110 Gy, followed by EBRT with 45 Gy (PI + EBRT). Intraoperative and post-implant dosimetric parameters 1 month after implantation were collected and analyzed. RESULTS: The numbers of patients implanted with free seeds and IBCL seeds were 14 (58.3%) and 10 (41.7%), respectively, in the PI group and 25 (65.8%) and 13 (34.2%), respectively, in the PI + EBRT group. In the PI group, although there were significant differences in prostate V100 (p = 0.003) and D90 (p = 0.009) and rectum V100 (p = 0.026) on intraoperative dosimetry, these differences were not found on post-implant dosimetry. In the PI + EBRT group, the dosimetric parameters of IBCL seeds, such as prostate V200 (p = 0.013) and V250 (p = 0.010) and urethra D30 (p = 0.038), were better than those of free seeds on intraoperative dosimetry. Furthermore, even on post-implant dosimetry, prostate D90 (p = 0.004), V150 (p = 0.001), and homogeneity index (HI, p = 0.001), as well as V200 (p = 0.001) and V250 (p = 0.020), and urethra D5 (p = 0.008) as well as D30 (p = 0.003) had a better dosimetric quality in IBCL seeds than in free seeds. There was no significant difference in the operation time between free seeds and IBCL seeds in each PI and PI + EBRT group. CONCLUSIONS: Our results reveal that greater dosimetric benefits could be obtained using IBCL seeds in the case of permanent implantation with a lower prescribed dose, such as PI + EBRT, rather than PI alone.

Glucose deprivation regulates the progranulin-sortilin axis in PC12 cells.

Progranulin (PGRN) is a growth factor implicated in several neurodegenerative diseases, such as frontotemporal lobar degeneration. Despite its important role in the central nervous system (CNS), the mechanisms controlling PGRN expression in the CNS are largely unknown. Recent evidence, however, suggested that several stressors, such as hypoxia, acidosis, or oxidative stress, induce PGRN expression. The present study was mainly aimed at determining whether and, if so, how glucose deprivation affects PGRN expression in PC12 cells. Initially, it was found that glucose deprivation gradually induced PGRN gene expression in PC12 cells. To elucidate the underlying molecular mechanisms, several intracellular signalings that were modified in response to glucose deprivation were examined. Both adenosine monophosphate kinase (AMPK) activation and changes in osmotic pressure, which are modified by extracellular glucose concentration, had no effect on PGRN gene expression; on the other hand, p38 activation in response to glucose deprivation played an important role in inducing PGRN gene expression. It was also found that expression of sortilin, a PGRN receptor implicated in PGRN endocytosis, was dramatically reduced by glucose deprivation. In contrast to glucose-dependent regulation of PGRN gene expression, AMPK activation played a central role in reducing sortilin expression. Overall, the present study suggests that the PGRN-sortilin axis is modulated by glucose deprivation via two distinct mechanisms. As PGRN is neuroprotective, this system may represent a new neuroprotective mechanism activated by glucose deprivation in the CNS.

Safe and successful birth following pelvic radiotherapy for rectal mucosa-associated lymphoid tissue lymphoma: a case report.

BACKGROUND: Mucosa-associated lymphoid tissue lymphomas can occur in various parts of the body, and half of mucosa-associated lymphoid tissue lymphomas occur in the gastrointestinal tract. Gastric mucosa-associated lymphoid tissue lymphoma is the most common lymphoma of the gastrointestinal tract and primary rectal mucosa-associated lymphoid tissue lymphoma is very rare. Because of the high radiosensitivity of mucosa-associated lymphoid tissue lymphomas, this condition can be controlled with radiotherapy of approximately 30 Gy alone. However, ovarian dysfunction as an adverse event of radiotherapy for pelvic lesions can become a problem in girls and women. We report a case of a 28-year-old woman with rectal mucosa-associated lymphoid tissue lymphoma who safely gave birth to a baby following 30.6 Gy radiotherapy to her whole rectum. CASE PRESENTATION: A 28-year-old Japanese woman became aware of bloody stools and was diagnosed as having Lugano I rectal mucosa-associated lymphoid tissue lymphoma. She was referred to our institute and initiated on radiotherapy. However, she expressed a desire to bear children. We used horizontally opposed pair fields for radiotherapy to minimize the irradiation to her endometrium and ovary. A total dose of 30.6 Gy was given in 17 fractions of 1.8 Gy by 10-Megavolt X-ray linear accelerator. As a result, one-third of her uterus and half of her ovary were outside the irradiation field. After approximately 1 year of treatment, positive pregnancy was confirmed and finally she safely gave birth to a baby girl without congenital abnormalities. CONCLUSIONS: This report provides hope for girls and women who have undergone irradiation for pelvic mucosa-associated lymphoid tissue lymphomas and who desire to bear children.

Preadministration of Hydrogen-Rich Water Protects Against Lipopolysaccharide-Induced Sepsis and Attenuates Liver Injury.

Despite significant advances in antibiotic therapy and intensive care, sepsis remains the most common cause of death in intensive care units. We previously reported that molecular hydrogen (H2) acts as a therapeutic and preventive antioxidant. Here, we show that preadministration of H2-dissolved water (HW) suppresses lipopolysaccharide (LPS)-induced endotoxin shock in mice. Drinking HW for 3 days before LPS injection prolonged survival in a mouse model of sepsis. The H2 concentration immediately increased in the liver but not in the kidney after drinking HW. The protective effects of the preadministration of HW on LPS-induced liver injury were examined. Twenty-four hours after LPS injection, preadministration of HW reduced the increase in both apoptosis and oxidative stress. Moreover, preadministration of HW enhanced LPS-induced expression of heme oxyganase-1 and reduced endothelin-1 expression. These results indicate the therapeutic potential of HW in preventing acute injury of the liver with attenuation of an increase in oxidative stress. HW is likely to trigger adaptive responses against oxidative stress.

The retrospective analysis of the relationship between prescribed dose and risk factor for seed migration in iodine-125 prostate brachytherapy.

PURPOSE: The aim was to determine the dose-specific incidence and predictors of seed loss/migration after permanent seed implantation (PI) for localized prostate cancer. MATERIALS AND METHODS: The records of 79 patients with T1c-T3a prostate cancer who underwent prostate brachytherapy with loose iodine-125 seeds were retrospectively reviewed. Of these patients, 33 with low or intermediate risk underwent PI with the prescribed dose of 160 Gy for the clinical target volume (CTV), and 46 with high risk underwent PI with 110 Gy for the CTV followed by external beam radiotherapy (EBRT) with 45 Gy. Each CTV was defined as a contoured prostate. After PI, the incidence of seed loss/migration was assessed by a series of radiographs. RESULTS: Seed migration occurred in 22 (0.479 %) of 4589 implanted seeds 1 month after implantation. In PI alone, the number of needles (P = 0.081) and the number of seeds (P = 0.071) showed a trend for a difference between those with and without seed loss. In PI + EBRT, there was a significant difference in the discrepancy between the seed numbers calculated by the nomogram and actually implanted (P = 0.032). CONCLUSIONS: It is suggested that the discrepancy in seed numbers might be the predictor for seed migration in PI with 110 Gy.

Impact of pretreatment whole-tumor perfusion computed tomography and 18F-fluorodeoxyglucose positron emission tomography/computed tomography measurements on local control of non-small cell lung cancer treated with stereotactic body radiotherapy.

This study aimed to investigate the correlation between the average iodine density (AID) detected by dual-energy computed tomography (DE-CT) and the maximum standardized uptake value (SUVmax) yielded by [18F] fluorodeoxyglucose positron emission tomography (18F-FDG PET) for non-small cell lung cancer (NSCLC) treated with stereotactic body radiotherapy (SBRT). Seventy-four patients with medically inoperable NSCLC who underwent both DE-CT and 18F-FDG PET/CT before SBRT (50‒60 Gy in 5‒6 fractions) were followed up after a median interval of 24.5 months. Kaplan-Meier analysis was used to determine associations between local control (LC) and variables, including AID, SUVmax, tumor size, histology, and prescribed dose. The median AID and SUVmax were 18.64 (range, 1.18-45.31) (100 µg/cm3) and 3.2 (range, 0.7-17.6), respectively. No correlation was observed between AID and SUVmax Two-year LC rates were 96.2% vs 75.0% (P = 0.039) and 72.0% vs 96.2% (P = 0.002) for patients classified according to high vs low AID or SUVmax, respectively. Two-year LC rates for patients with adenocarcinoma vs squamous cell carcinoma vs unknown cancer were 96.4% vs 67.1% vs 92.9% (P = 0.008), respectively. Multivariate analysis identified SUVmax as a significant predictor of LC. The 2-year LC rate was only 48.5% in the subgroup of lower AID and higher SUVmax vs >90% (range, 94.4-100%) in other subgroups (P = 0.000). Despite the short follow-up period, a reduction in AID and subsequent increase in SUVmax correlated significantly with local failure in SBRT-treated NSCLC patients. Further studies involving larger populations and longer follow-up periods are needed to confirm these results.

Prognostic impact of average iodine density assessed by dual-energy spectral imaging for predicting lung tumor recurrence after stereotactic body radiotherapy.

The purpose of this study was to investigate the prognostic significance of average iodine density as assessed by dual-energy computed tomography (DE-CT) for lung tumors treated with stereotactic body radiotherapy (SBRT). From March 2011 to August 2014, 93 medically inoperable patients with 74 primary lung cancers and 19 lung metastases underwent DE-CT prior to SBRT of a total dose of 45-60 Gy in 5-10 fractions. Of these 93 patients, nine patients had two lung tumors. Thus, 102 lung tumors were included in this study. DE-CT was performed for pretreatment evaluation. Regions of interest were set for the entire tumor, and average iodine density was obtained using a dedicated imaging software and evaluated with regard to local control. The median follow-up period was 23.4 months (range, 1.5-54.5 months). The median value of the average iodine density was 1.86 mg/cm(3) (range, 0.40-9.27 mg/cm(3)). Two-year local control rates for the high and low average iodine density groups divided by the median value of the average iodine density were 96.9% and 75.7% (P = 0.006), respectively. Tumors with lower average iodine density showed a worse prognosis, possibly reflecting a hypoxic cell population in the tumor. The average iodine density exhibited a significant impact on local control. Our preliminary results indicate that iodine density evaluated using dual-energy spectral CT may be a useful, noninvasive and quantitative assessment of radio-resistance caused by presumably hypoxic cell populations in tumors.

Clinical outcome of stereotactic body radiotherapy for primary and oligometastatic lung tumors: a single institutional study with almost uniform dose with different five treatment schedules.

BACKGROUND: To evaluate clinical outcomes of stereotactic body radiotherapy (SBRT) for localized primary and oligometastatic lung tumors by assessing efficacy and safety of 5 regimens of varying fraction size and number. METHODS: One-hundred patients with primary lung cancer (n = 69) or oligometastatic lung tumors (n = 31), who underwent SBRT between May 2003 and August 2010, were included. The median age was 75 years (range, 45-88). Of them, 98 were judged to have medically inoperable disease, predominantly due to chronic illness or advanced age. SBRT was performed using 3 coplanar and 3 non-coplanar fixed beams with a standard linear accelerator. Fraction sizes were escalated by 1 Gy, and number of fractions given was decreased by 1 for every 20 included patients. Total target doses were between 50 and 56 Gy, administered as 5-9 fractions. The prescribed dose was defined at the isocenter, and median overall treatment duration was 10 days (range, 5-22). RESULTS: The median follow-up was 51.1 months for survivors. The 3-year local recurrence rates for primary lung cancer and oligometastasis was 6 % and 3 %, respectively. The 3-year local recurrence rates for tumor sizes ≤3 cm and >3 cm were 3 % and 14 %, respectively (p = 0.124). Additionally, other factors (fraction size, total target dose, and BED10) were not significant predictors of local control. Radiation pneumonia (≥ grade 2) was observed in 2 patients. Radiation-induced rib fractures were observed in 22 patients. Other late adverse events of greater than grade 2 were not observed. CONCLUSION: Within this dataset, we did not observe a dose response in BED10 values between 86.4 and 102.6 Gy. SBRT with doses between 50 and 56 Gy, administered over 5-9 fractions achieved acceptable tumor control without severe complications.

Nanofiltration concentration of extracellular glutathione produced by engineered Saccharomyces cerevisiae.

This study aimed to optimize extracellular glutathione production by a Saccharomyces cerevisiae engineered strain and to concentrate the extracellular glutathione by membrane separation processes, including ultrafiltration (UF) and nanofiltration (NF). Synthetic defined (SD) medium containing 20 g L(-1) glucose was fermented for 48 h; the fermentation liquid was passed through an UF membrane to remove macromolecules. Glutathione in this permeate was concentrated for 48 h to 545.1 ± 33.6 mg L(-1) using the NF membrane; this was a significantly higher concentration than that obtained with yeast extract peptone dextrose (YPD) medium following 96 h NF concentration (217.9 ± 57.4 mg L(-1)). This higher glutathione concentration results from lower cellular growth in SD medium (final OD600 = 6.9 ± 0.1) than in YPD medium (final OD600 = 11.0 ± 0.6) and thus higher production of extracellular glutathione (16.0 ± 1.3 compared to 9.2 ± 2.1 mg L(-1) in YPD medium, respectively). Similar fermentation and membrane processing of sweet sorghum juice containing 20 g L(-1) total sugars provided 240.3 ± 60.6 mg L(-1) glutathione. Increased extracellular production of glutathione by this engineered strain in SD medium and subsequent UF permeation and NF concentration in shortend time may help realize industrial recovery of extracellular glutathione.

Stereotactic body radiotherapy for lung metastases as oligo-recurrence: a single institutional study.

The purpose of this study was to investigate clinical outcomes following stereotactic body radiotherapy (SBRT) for lung metastases as oligo-recurrence. From May 2003 to June 2014, records for 66 patients with 76 oligo-recurrences in the lungs treated with SBRT were retrospectively reviewed. Oligo-recurrence primary sites and patient numbers were as follows: lungs, 31; colorectal, 13; head and neck, 10; esophagus, 3; uterus, 3; and others, 6. The median SBRT dose was 50 Gy (range, 45-60 Gy) administered in a median of 5 (range, 5-9) fractions. All patients received SBRT, with no acute toxicity. Surviving patients had a median follow-up time of 36.5 months. The 3-year rates of local control, overall survival and disease-free survival were 90.6%, 76.0% and 53.7%, respectively. Longer disease-free interval from initial treatment to SBRT, and non-colorectal cancer were both associated with favorable outcomes. Disease progression after SBRT occurred in 31 patients, most with distant metastases (n = 24) [among whom, 87.5% (n = 21) had new lung metastases]. Among these 21 patients, 12 were judged as having a second oligo-recurrence. Additional SBRT was performed for these 12 patients, and all 12 tumors were controlled without disease progression. Three patients (4.5%) developed Grade 2 radiation pneumonitis. No other late adverse events of Grade ≥2 were identified. Thus, SBRT for oligo-recurrence achieved acceptable tumor control, with additional SBRT also effective for selected patients with a second oligo-recurrence after primary SBRT.