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Glioblastoma (GBM) is a rapidly growing and most life-threatening malignant brain tumor. The significance of early treatment to the clinical outcomes of patients with GBM is unclear.To determine whether early diagnosis and surgery improve the preoperative and postoperative Karnofsky performance status (KPS) and prognosis of patients with GBM.Data of isocitrate dehydrogenase-wildtype patients with GBM treated at our institution between January 2010 and December 2019 were reviewed. Patients were classified into early or late diagnosis groups with a threshold of 14 days from initial symptoms. In addition, patients were divided into early, intermediate, and late surgery groups with thresholds of 21 and 35 days. Representative symptoms and patient prognoses were examined.Of 153 patients, 72 and 81 were classified into the early and late diagnosis groups. The median tumor volume was significantly smaller in the former group. The proportion of patients with preoperative KPS scores 90 was 48.6% and 29.6% in the early and late diagnosis groups ( P = .016). The early, intermediate, and late surgery groups included 43, 24, and 86 patients. The median overall survival was significantly longer in the early surgery group than in the late surgery group (28.4 vs 18.7 months, P = .006). Multivariate analysis demonstrated that significant predictors of shorter survival included extent of tumor resection (partial or biopsy), preoperative and postoperative KPS 60, and O6-methylguanine-DNA-methyltransferase promoter status (unmethylated).Early diagnosis within 2 weeks and surgical interventions within 3 weeks from the symptom onset are associated with prolonged patient survival. Early GBM treatment will benefit patients with GBM.

Purpose: The neurological status of glioblastoma (GBM) patients rapidly deteriorates. We recently demonstrated that early diagnosis and surgery within three weeks from the initial symptoms are associated with improved survival. While GBM is a semi-urgent disease, the prehospital behaviors and clinical outcomes of GBM patients are poorly understood. We aimed to disclose how prehospital patient behavior influences the clinical outcomes of GBM patients. Methods: IDH-wildtype GBM patients treated at our institution between January 2010 and December 2019 were reviewed. Patients were divided into two groups: neurosurgeon and non-neurosurgeon groups, based on the primary doctor whom patients sought for an initial evaluation. Patient demographics and prognoses were examined. Results: Of 170 patients, 109 and 61 were classified into the neurosurgeon and non-neurosurgeon groups, respectively. The median age of neurosurgeon group was significantly younger than the non-neurosurgeon group (61 vs. 69 years old, P = 0.019) and in better performance status (preoperative KPS scores ≥ 80: 72.5% vs. 55.7%, P = 0.027). The neurosurgeon group exhibited a significantly shorter duration from the first hospital visit to the first surgery than the non-neurosurgeon group (18 vs. 29 days, P < 0.0001). Furthermore, the overall survival of the neurosurgeon group was significantly more prolonged than that of the non-neurosurgeon group (22.9 vs. 14.0 months, P = 0.038). Conclusion: Seeking an initial evaluation by a neurosurgeon was associated with prolonged survival in GBM patients. A short duration from the first hospital visit to the first surgery is essential in enhancing GBM patient prognosis.

Purpose We evaluated magnetic resonance imaging (MRI) findings of dedifferentiated endometrial carcinoma (DEC), comprising undifferentiated carcinoma and low-grade endometrioid carcinoma. Materials and methods We recruited 11 patients with pathologically proven DEC treated at our institute. We evaluated primary lesion size, location and signal intensity on MRI, and prognosis. MRI and pathological findings were compared in eight resected patients. Results Primary tumors ranged from 16 to 206 mm in diameter. DEC was located at the endometrium in 9 of the 11 patients; the remaining two patients showed diffuse involvement of the enlarged myometrium. These two patients with diffuse involvement type died within 4 months. Of the eight patients who underwent resection, seven had macroscopic intratumoral hemorrhage and six showed a high signal on T1-weighted images or low signal on T2-weighted images. Of the eight resected patients, four had tumor necrosis > 25% and tumor size > 5 cm. In these patients, necrosis appeared as nonenhanced areas on contrast-enhanced MRI. Conclusion MRI findings of DEC showed two patterns: mass-forming type and diffuse myometrial type with poor prognosis. Most patients with DEC had intratumoral hemorrhage, and large tumors (> 5 cm) had gross necrosis, which appeared as nonenhanced areas on contrast-enhanced MRI.

Background: Nelarabine is an effective treatment for T-cell acute lymphoblastic leukemia/lymphoma. Myelopathy is a problematic adverse event associated with nelarabine. The mechanism leading to myelopathy is unclear. Diagnostic methods and therapy for nelarabine-induced myelopathy have not been established.Case presentation: Three patients who received allogeneic hematopoietic cell transplantation (allo-HCT) after nelarabine administration at the National Cancer Center Hospital from December 2014 to March 2021 developed myelopathy. They developed myelopathy 20 days before allo-HCT, 12 days after allo-HCT, and 29 days after allo-HCT, respectively. The intervals from last nelarabine administration to onset of myelopathy were 41 days, 121 days, and 47 days, respectively. The initial symptom was paresthesia in the lower legs in all patients. In two of three patients, magnetic resonance imaging showed lesions in the dorsal column or medulla oblongata, a characteristic finding of nelarabine-induced myelopathy that was similar to findings in mitochondrial diseases. We treated all three patients with intravenous immunoglobulin and methylprednisolone, but all became unable to walk. One patient died on day 101 due to the progression of neurotoxicity. In the other two patients, neurological symptoms spontaneously improved. One patient is alive and became able to walk with a cane despite some muscle weakness in his lower extremities by 8 months after allo-HCT. The other patient was able to move around in a wheelchair but died of mucormycosis on day 476 after allo-HCT. Postmortem autopsy of two patients showed spongiosis of the posterior funiculus. One patient also had the same finding in the medulla oblongata.Conclusions: Nelarabine is a valid treatment option. However, these cases suggest that allo-HCT can worsen nelarabine-induced myelopathy, a potentially fatal condition for which there is no effective treatment. Elucidation of the mechanism and establishment of diagnostic methods and therapies for nelarabine-induced myelopathy are needed.

We herein report a case of encephalitis in a 42-year-old woman with hepatocellular carcinoma following atezolizumab plus bevacizumab therapy. After two weeks of treatment, she was admitted for a high fever, impaired consciousness, and convulsive seizure refractory to diazepam. Magnetic resonance imaging revealed a hyperintense splenial lesion. A cerebrospinal fluid test excluded malignancy and infection. These findings were highly suggestive of a diagnosis of encephalitis due to atezolizumab, an immune-related adverse event. Steroid pulse therapy improved the fever and seizure. However, her incomplete right-sided paralysis and aphasia persisted. This is the first case report of encephalitis caused by atezolizumab plus bevacizumab therapy for hepatocellular carcinoma.

Our previous study by Murakami N, Mori T, Nakamura S, Yoshimoto S, Honma Y, Ueno T, Kobayashi K, Kashihara T, Takahashi K, Inaba K, Okuma K, Igaki H, Nakayama Y, Itami J. (J Radiat Res. 2019 Jul 30. pii: rrz053. doi: 10.1093/jrr/rrz053. [Epub ahead of print]) showed that strong expression of epithelial cell adhesion molecule (EpCAM) was associated with radiation resistance in head and neck squamous cell cancer patients (SCC). In this study, the prognostic impact of histopathologic features including EpCAM for nasopharyngeal cancer (NPC) patients was investigated. Since 2009, our institution has performed chemoradiation for locally advanced NPC patients with intensity modulated radiation therapy (IMRT). Tri-weekly adjuvant cisplatin (CDDP, 80 mg/m2) was administered concurrently with definitive radiation therapy 70 Gy in 35 fractions. One month after radiation therapy, adjuvant chemotherapy of three cycles of CDDP/5 fluorouracil (5-FU) was administered. Using a pretreatment biopsy specimen, EBV-encoded small RNA in situ hybridization (EBER-ISH), EpCAM, p16 and p53 were assessed by immunohistochemical analysis. Between May 2009 and September 2017, 51 NPC patients received definitive radiation therapy. Five, 13, 17 and 16 patients were staged as I, II, III and IV, respectively. The median follow-up period for alive patients was 31.1 months (12.4–109.7 months). Three-year overall survival (OS), progression-free survival (PFS) and locoregional control (LRC) were 87.1, 57.1 and 85.7%, respectively. EpCAM, p16 and p53 were not associated with PFS, OS nor LRC. Three-year PFS for patients with keratinizing and non-keratinizing SCC were 25 and 60.5%, respectively (P = 0.033, hazard ratio 4.851 (95% confidence interval 1.321–17.814)).Prognosis of NPC patients with keratinizing SCC was worse than non-keratinizing SCC patients, suggesting a biological difference between the two types of tumor.

Purpose The validity of the risk classification according to Ang for human papillomavirus (HPV)-related oropharyngeal squamous cell carcinoma (OPSCC) remains to be studied in patients treated by methods other than chemoradiotherapy and in Japanese patients. In this study, the validity of Ang's risk classification was studied in Japanese patients treated using various methods, including surgery.Material and Method Between 2010 and 2018, 122 patients with HPV-related OPSCC stages III and IV according to the TNM classification 7th edition (TNM-7) were treated curatively at a single institution in Japan. The median age was 62.7 years. Sixty-seven patients (54.9%) were classified as stage I according to the TNM 8th edition (TNM-8). Over 50% of the patients underwent surgery with or without adjuvant therapy. The influence of multiple factors on survival was determined.Results Age, amount of smoking, secondary cancer, and N-stage according to the TNM-7 significantly influenced survival. Ang's risk classification was also predictive of prognosis, but if 30 pack-years (PYs) instead of 10 PYs is employed to dichotomize the amount of smoking, the new risk classification can significantly better predict prognosis. According to the new risk classification, favorable and unfavorable risk patients showed 5-year progression-free survival, disease-specific survival, and overall survival rates of 72.7% and 35.9%, 94.6% and 76.2%, and 92.6% and 62.7%, respectively.Conclusions Even in patients treated by methods other than chemoradiotherapy and in Japanese patients, the combination of the amount of smoking and neck node status is useful in prognosis prediction.

[Purpose] The validity of the risk classification according to Ang for human papillomavirus (HPV)-related oropharyngeal squamous cell carcinoma (OPSCC) remains to be studied in patients treated by methods other than chemoradiotherapy and in Japanese patients. In this study, the validity of Ang's risk classification was studied in Japanese patients treated using various methods, including surgery. [Material and Method] Between 2010 and 2018, 122 patients with HPV-related OPSCC stages III and IV according to the TNM classification 7th edition (TNM-7) were treated curatively at a single institution in Japan. The median age was 62.7 years. Sixty-seven patients (54.9%) were classified as stage I according to the TNM 8th edition (TNM-8). Over 50% of the patients underwent surgery with or without adjuvant therapy. The influence of multiple factors on survival was determined. [Results] Age, amount of smoking, secondary cancer, and N-stage according to the TNM-7 significantly influenced survival. Ang's risk classification was also predictive of prognosis, but if 30 pack-years (PYs) instead of 10 PYs is employed to dichotomize the amount of smoking, the new risk classification can significantly better predict prognosis. According to the new risk classification, favorable and unfavorable risk patients showed 5-year progression-free survival, disease-specific survival, and overall survival rates of 72.7% and 35.9%, 94.6% and 76.2%, and 92.6% and 62.7%, respectively. [Conclusions] Even in patients treated by methods other than chemoradiotherapy and in Japanese patients, the combination of the amount of smoking and neck node status is useful in prognosis prediction.

A 69-year-old female with recurrent stage IV squamous cell lung carcinoma and metastatic abdominal lymph node but not bone metastases was being treated with pembrolizumab. Four months after starting the recurrent treatment, the tumour reduced in size but she began to complain of back pain and palmar rash. A bone scan showed uptake lesions in the left sternocostal joints and vertebrae, while spine magnetic resonance imaging (MRI) showed multiple lesions in the thoracic vertebrae. Her heterogeneous lesions, such as skin and multiple bone manifestations, were comprehensively diagnosed as SAPHO syndrome by different experts. Furthermore, the SAPHO syndrome was suspected to be an immune-related adverse event induced by pembrolizumab, and pembrolizumab withdrawal and prednisolone treatment were performed. Subsequently, her symptoms improved and the follow-up imaging findings showed that the bone lesions had almost disappeared. This case demonstrates that SAPHO syndrome mimicking bone metastases developed during treatment with pembrolizumab. SAPHO syndrome is rare and bone lesions related to the disease may be misdiagnosed as bone metastases. Therefore, it is important in the future for various physicians to have a better understanding of SAPHO syndrome and to consider the potential relationship between this disease and immunotherapy.

Background and PurposeMost locoregional recurrences after definitive radiotherapy for head and neck squamous cell carcinoma (HNSCC) develop “in-field.” Dose escalation while sparing organs at risk can be a good solution for improving local control without increasing adverse effects. This study investigated the safety and effectiveness of volumetric modulated arc therapy (VMAT) using intentionally internal high-dose policy (IIHDP) to treat neck lymph node metastases (NLNM) ≥ 2 cm in HNSCC patients.Materials and MethodsWe analyzed 71 NLNM from 51 HNSCC patients who had received definitive radiotherapy to treat NLNM ≥ 2 cm using the VMAT technique in our institution between February 2017 and August 2019. Thirty-seven NLNM from 25 patients were treated using IIHDP VMAT (group A), and 34 NLNM from 27 patients were treated with homogeneous-dose distribution policy (HDDP) VMAT (group B). One patient with three NLNM had one lymph node assigned to group A and the other two to group B. Adverse events and local recurrence-free survival (LRFS) was compared between the two groups.ResultsIn the median follow-up period of 527 days, there were no significant differences between the groups in terms of dermatitis or mucositis ≥ grade 2/3, but LRFS was significantly longer in group A (p = 0.007). In the Cox regression analysis after adjustment for the propensity score, group A also showed an apparently superior LFRS.ConclusionOur initial experience of IIHDP VMAT suggested that IIHDP VMAT to treat HNSCC neck lymph node metastases measuring ≥ 2 cm was feasible and possibly led to better local control than HDDP VMAT.

Purpose Adjuvant durvalumab has become a standard treatment after chemoradiation therapy for patients with locally advanced non-small cell lung cancer (LA-NSCLC). Accordingly, predicting radiation pneumonitis (RP) requiring steroidal treatment (steroid-RP) is of utmost importance because steroidal administration is reported to weaken the effectiveness of immunotherapy. However, grade 2 RP was used as an index of RP in previous studies, but it is an ambiguous definition because it includes not only steroid-RP but also a mild cough requiring only a cough medicine. Therefore, in this study, steroid-RP was used for evaluating RP, and the purpose of this study was to investigate predictive factors of steroid-RP, including original simple interstitial lung abnormality scores (ILASs). Methods and Materials A total of 145 patients with LA-NSCLC who received definitive radiation therapy (DRT) in our institution from January 2014 to May 2017 were identified. Original ILASs, performance status, age, respiratory function, Brinkman index, concurrent administration of chemotherapy, and dose–volume histogram metrics of the lung were analyzed to evaluate their association with steroid-RP. Additionally, 3 diagnostic radiologists evaluated the patients’ pre-DRT chest computed tomography images and determined the simple ILASs. ILASs were rated as follows: 0: none; 1: abnormality without honeycombing (ground-glass attenuation, fine reticular opacity, and microcysts); and 2: honeycombing. Results The median follow-up period was 729 days. Thirty-one patients (21.4%) experienced steroid-RP. In the univariate analysis, lung V5/V10/VS5, Brinkman index, and ILASs were significant predictive factors of steroid-RP. Additionally, multivariate analysis including Brinkman index ≥840, lung V5 ≥37%, and an ILAS ≥1 revealed that only an ILAS (P = .001) was an independent predictive factor of steroid-RP. Conclusions The original simple ILAS was an easy-to-use tool and a significant predictive factor of steroid-RP in DRT in patients with LA-NSCLC.

Background In definitive radiation therapy for prostate cancer, the SpaceOAR® System, a hydrogel spacer, is widely used to decrease the irradiated dose and toxicity of rectum. On the other hand, periprostatic abscesses formation and rectal perforation are known as rare adverse effects of SpaceOAR. Nevertheless, there is a lack of reports clarifying the association between aggravation of abscesses and radiation therapy, and hyperbaric oxygen therapy (HBOT) is effective for a peri-SpaceOAR abscess and rectal perforation. Case presentation We report a case of a 78-year-old high-risk prostate cancer patient. After SpaceOAR insertion into the correct space, he started to receive external beam radiation therapy (EBRT). He developed a fever, perineal pain and frequent urination after the completion of EBRT, and the magnetic resonance imaging (MRI) revealed a peri-SpaceOAR abscess. Scheduled brachytherapy was postponed, administration of antibiotics and opioid via intravenous drip was commenced, and transperineal drainage was performed. After the alleviation of the abscess, additional EBRT instead of brachytherapy was performed with MRI-guided radiation therapy (MRgRT). On the last day of the MRgRT, perineal pain reoccurred, and MRI and colonoscopy detected the rectal perforation. He received an intravenous antibiotics drip and HBOT, and fully recovered from the rectal perforation. Conclusions Our report indicates that EBRT can lead to a severe rectum complication by causing inflammation for patients with a peri-SpaceOAR abscess. Furthermore, HBOT was effective for the peri-SpaceOAR abscess and rectal perforation associated with EBRT.

Background: Validity of the risk classification by Ang for human papillomavirus (HPV)-related oropharyngeal squamous cell carcinoma (OPSCC) remains to be studied in the patients treated by modalities other than chemoradiotherapy and in Japanese patients. Materials and Methods: Between 2010 and 2018, 122 patients with HPV-related OPSCC in stages III and IV by the TNM classification 7th edition (TNM-7) were treated curatively at a single institution in Japan. The median age was 62.7 years. Over 50% of the patients underwent surgery with or without adjuvant therapy. The influence of multiple factors on survival was analyzed. Results: The amount of smoking dichotomized at 10 pack-year, which was used in Ang’s risk classification, was not predictive of prognosis, and Ang’s risk classification was not significantly influential on prognosis in multivariate analysis. In the patients treated with definitive radiation therapy, Ang’s risk classification was not predictive of the prognosis in univariate analysis. The impact of smoking was significant only in the patients undergoing the definitive operation. Conclusions: Ang’s risk classification was not robust in predicting the prognosis of general Japanese HPV-related OPSCC patients. The amount of smoking might have different prognostic influences depending on the therapeutic method.

[Purpose] Tobacco smoking has been reported to influence the prognosis of human papilloma virus (HPV)-related orophageyngeal squamous cell carcinoma (OPSCC). However, it remains to be studied whether tobacco smoking equally affects the patients treated by various modalities. [Material and Method] From 2010 through 2018, 241 patients with OPSCC were treated in a single institution, out of which 144 patients had HPV-related OPSCC. P16 immunohistochemical staining was used as a surrogate of HPV infection. Two patients was excluded because of inadequate radiation dose, and the remaining 142 patients were the subject of this study. Median age was 63.8 years and more than 80% were male. More than 70% were smokers or ex-smokers with a median pack year of 17.3. Eighty-seven patients (61.3%) were classified as stage I.[Results] For all 142 patients with HPV-related OPSCC, overall survival (OS) and disease-specific survival (DSS) were 87.0% and 93.4% in 3 years, respectively. There were no differences of OS and DSS according to the stages by 8th edition of tumor, node, and metastasis (TNM) classification and the primary sites. OS and DSS were different by the amount of tobacco smoking expressed in pack year (PY) > 30 and < 30. Also the presence of secondary cancer impacted OS. However, the influence of the amount of tobacco smoking was reduced in the patients treated by radiation therapy. [Conclusions] The impact of tobacco smoking upon the prognosis of HPV-related OPSCC seems to be dependent upon therapeutic modalities.

Background In definitive radiation therapy for prostate cancer, SpaceOAR, a hydrogel spacer, is widely used to decrease irradiated dose and toxicity of rectum. On the other hand, periprostatic abscess formation is known as a rare adverse effect of SpaceOAR. There is a lack of reports clarifying the association between aggravation of abscesses and radiation therapy, and whether SpaceOAR insertion succeeded or not. Case presentation We report a case of a 78-year-old high-risk prostate cancer patient. After SpaceOAR insertion into the correct space, he started to receive external beam radiation therapy (EBRT). He developed a fever, perineal pain and frequent urination after the completion of EBRT, and the magnetic resonance imaging (MRI) revealed a peri-SpaceOAR abscess. Scheduled brachytherapy was postponed, administration of antibiotics and opioid via intravenous drip was commenced, and transperineal drainage was performed. After the alleviation of the abscess, additional EBRT instead of brachytherapy was performed with MRI-guided radiation therapy (MRgRT). On the last day of the MRgRT, perineal pain reoccurred, and MRI and colonoscopy detected the rectal perforation. He received an intravenous antibiotics drip and hyperbaric oxygen therapy (HBOT), and fully recovered from the rectal perforation. Conclusions Our report indicates that EBRT can lead to severe rectum complication by causing inflammation for patients with a peri-SpaceOAR abscess. Furthermore, HBOT was effective for the peri-SpaceOAR abscess and rectal perforation associated with EBRT.

There is an unmet need for improving survival outcomes of locally advanced nasopharyngeal carcinoma, for example, T4/ N3 stage disease. To this end, we administered induction chemotherapy (IC) with TPF (docetaxel, cisplatin, and fluorouracil) because this stage of disease is associated with a high risk of recurrence and is difficult to control with standard treatments, such as chemoradiotherapy (CRT) alone or CRT followed by adjuvant chemotherapy. The aim of this retrospective single-center study was to clarify the short-term outcomes of locally far-advanced nasopharyngeal carcinoma patients treated with IC-TPF, followed by CRT with cisplatin. Data from 11 patients were extracted from our database, indicating that the overall response rate to IC-TPF, clinical complete response rate after CRT, 1-year progression-free survival, and 1-year overall survival were 73%, 91%, 68%, and 89%, respectively. Hematological toxicity was the most common adverse event reported during IC-TPF with 64% of patients suffering grade 3 or 4 neutropenia, 55% grade 3 or 4 leucopenia and 9% febrile neutropenia. Despite the small number of patients, these data are important because there is a limited number of studies investigating IC-TPF followed by CRT in Japanese patients. This pilot study provides some indication of the short-term effectiveness and toxicity of this therapeutic approach, which may be superior to standard treatments. Long-term follow-up is warranted to assess the effectiveness of IC-TPF in terms of clinical outcome and late-phase toxicity.

A greenhouse experiment was conducted to study the effects of saline water irrigation and soil salinity on the growth of kochia (Kochia scoparia (L.) Schrad.) and alfalfa (Medicago sativa L.). The alfalfa production was low, and half of the plants withered and died under soil electrical conductivity of ≥4 dS m−1. However, high salinity did not affect kochia growth. The mechanism of sodium absorption differs between kochia and alfalfa. Kochia has a salt-tolerance mechanism whereby the sodium concentration in the plant does not increase, regardless of the environmental conditions of the soil. However, the sodium concentration in alfalfa increases with increasing concentrations of sodium in the soil. Accordingly, changes were observed in the salt composition of alfalfa that harmed the plant. Although good kochia growth was observed in soil with limited water irrigation, it is difficult to grow alfalfa using the same quantity and salinity of irrigation water as used for kochia. Kochia can be cultivated using limited water and in highly saline soil in arid and semiarid regions. Furthermore, since kochia cultivation requires limited irrigation water, the plant may suppress the increase in the salinity of the soil and irrigation water. Therefore, in saline soil in arid and semiarid regions, kochia may be promising as an effective forage crop substitute for alfalfa.

Macroscopic assessment of the pubic symphysis is commonly used for age estimation because its surface changes over time. However, postmortem computed tomography (PMCT), a method several forensic medical departments and institutes have begun to adopt, has the potential to simplify the information gathering process from the pelvic bone without requiring soft tissue removal. Some studies have previously evaluated the use of three-dimensional images of the pubic symphysis, but because of variance in the graphics processing among image analysis software packages, certain differences have been observed between these studies. Therefore, in this study, the PMCT findings of 199 subjects of known age and sex were retrospectively reviewed to examine the feasibility of age estimation using planar images of the pubic bones and soft tissue. The coronal and axial sectional images were observed at the center of the symphyseal surface, and the pubic bone length and thickness of the connective tissue of the pubic symphysis were measured at each slice. Our results revealed a significant positive correlation between the length of the pubic bone of the coronal section and age, suggesting that the use of a cutoff value for pubic bone length might be feasible for age estimations. In addition, the thickness of the connective tissue tended to narrow over time. Although the prediction interval range of planar images obtained by PMCT was major and is not usable in practice at this moment, it may still be a useful tool if used in conjunction with other findings obtained by PMCT.

We report fatal cases of cyclobarbital poisoning. A Japanese husband and wife, 89 and 91 years old, respectively, were found dead in their locked home. The postmortem blood concentrations of cyclobarbital in the husband (68 μg/ml) and wife (70 μg/ml) were measured by gas chromatography–mass spectrometry and clearly exceeded the therapeutic range. In the absence of other remarkable autopsy findings, the deaths in these two cases were determined to be caused by cyclobarbital poisoning, which is extremely rare. Despite its current unavailability, cyclobarbital was shown to be the cause of death, emphasizing the importance of toxicological screening for cyclobarbital.

This paper introduces a new triage simulation method for use in the design phase of disaster triage method for vulnerable people. The proposed method is an online scenario-based triage simulation incorporates the Delphi method. The method was assessed to determine its effectiveness for obtaining knowledge to improve the design of a new triage method. The result showed that the method is effective for identifying the appropriate triage, consideration points, and the cases for which the appropriate triage is difficult to determine.

Population aging is rapidly advancing in numerous parts of the world and, accordingly, the prevalence of Alzheimer's disease (AD) is rising. The safety of donepezil (DPZ), which is used for AD treatment, has been established in clinical trials. However, some studies have indicated that DPZ may be associated with severe cardiac side effects, and excessive doses may induce toxicity-related symptoms or death. Therefore, the measurement of blood DPZ levels is important for the postmortem investigation of related causes of death. However, postmortem drug concentrations in the blood may not always reflect those obtained antemortem because of the postmortem redistribution (PMR) of drugs. Therefore, the aim of this study was to investigate the potential PMR of DPZ using a rat model. The DPZ concentration was measured using a validated HPLC/Q-TOF-MS system in cardiac and peripheral blood, and in the brain, lungs, myocardium, liver, and thigh muscle at different postmortem intervals (0, 1, 3, 6, 12, and 24h). Overall, the DPZ tissue to peripheral blood ratio decreased throughout the postmortem period. Furthermore, the DPZ concentration increased in the peripheral and cardiac blood but decreased in both of the lungs, postmortem. Furthermore, the blood pH was significantly lowered. We used a perfusion approach to examine the rat lung and heart to further investigate the relationship between the pH and DPZ release from the lungs. The outflow concentrations when the inflow pH changed from 7.4 to 5.5 were approximately 2-fold higher than the inflow pH fixed 7.4. These findings suggest that the antemortem accumulated DPZ in the lungs is released into the pulmonary blood owing to postmortem acidification of blood, and subsequently flows into the cardiac blood, leading to the observed increase in concentration. Although we could not determine the underlying mechanism, we confirmed that PMR occurs similarly in the cardiac and peripheral blood.

Easy oocyte detection in living specimens benefits various developmental biology and environmental toxicology studies. One of the earliest markers of sex differentiation in medaka (Oryzias latipes) is oocyte development. Within the field of toxicology, a simple detection method for induced oocyte in the testis (testis-ova) as a result of endocrine disruption is necessary. In this study we produced transgenic medaka whose oocytes were labeled with fluorescent proteins using the regulatory region of the 42Sp50 gene, an isoform of polypeptide elongation 1-alpha. Short (201 nt) 5'- and 3'-flanking regions were sufficient for reporter gene expression. GFP expression was first observed in female germ cells approximately 5 days post-hatching. In the mature ovaries, germ cells showed such intense fluorescence that the fluorescence was observed from outside the body wall. In contrast, very faint fluorescence was observed in the mature testes. Testis-ova, oocytes artificially induced in the testes, were also labeled with GFP. These findings indicate through the use of transgenic medaka, that detection of female germ cells was straightforward and this transgenic medaka model proves useful for tracking female germ cells in developmental and toxicological studies.

Mammalian pigment cells produce melanin as the main pigment. Melanocytes, one of the two types of mammalian pigment cells, differentiate from the neural crest and migrate to a variety of organs during development. Melanocytes exist not only in the skin but also in other sites such as the cochlea where they are essential for hearing. Mitf(mi-bw) is one of the known recessive alleles of the mouse microphthalmia-associated transcription factor (Mitf) locus, which is essential for the development of pigment cells. Homozygous Mitf(mi-bw)/Mitf(mi-bw) mice have a completely white coat with black eyes and are deaf due to the lack of melanocytes. By comparing gene expression profiles in cochleae of wild-type and Mitf(mi-bw)/Mitf(mi-bw) mice, we now demonstrate the specific expression of glutathione S-transferase alpha 4 (Gsta4) in the stria vascularis. Gsta4 encodes one of the cytosolic glutathione S-transferases (GSTs) which participate in detoxification processes of many tissues. This gene is specifically expressed in intermediate cells of the stria vascularis, suggesting a novel function for cochlear melanocytes. Moreover, among mammalian pigment cells, expression of Gsta4 was restricted to cochlear melanocytes, suggesting that melanocytes in various tissues differentiate from one another depending on their location.

We report three cases of percutaneous osteoplasty for the treatment of hypervascular bone metastasis. Four hypervascular bone metastases were treated in three consecutive patients by percutaneous osteoplasty under fluoroscopic or computed tomographic guidance. Primary malignant tumors included pheochromocytoma and renal cell carcinoma. Pain relief after osteoplasty was achieved in all three patients. There was no major complication. Projectile bleeding and subcutaneous hematoma were noted during or after osteoplasty but were easily controlled conservatively. Percutaneous osteoplasty for hypervascular bone metastases is not only a highly effective but also a minimally invasive technique that provides immediate pain relief without major complication.

Donepezil (DPZ) is an acetylcholine-esterase inhibitor currently used as the frontline drug to treat Alzheimer's disease. The aim of this study was to investigate the possibility of postmortem redistribution (PMR) of DPZ, which could complicate the determination of cause of death in medico-legal cases. Additionally, metabolic enzyme DNA polymorphism, drug-drug interaction and the presence of lesions in metabolic and egestion organs were examined to eliminate the possibility of a high antemortem DPZ concentration. Subsequently, the average DPZ concentration of four sites of peripheral blood (right and left femoral artery and vein) was compared with central blood and liver DPZ concentrations in seven postmortem cases. DPZ concentrations ranged from 0.02 to 0.45μg/mL in the peripheral blood, 0.09-0.4μg/mL in central blood, and from 1.2 to 6.7μg/kg in the liver. In most specimens, the concentrations were higher than the therapeutic range (approximately 0.030-0.075μg/mL). DPZ central blood to peripheral blood (C/P) ratios averaged 1.73±1.02 (±standard deviation) while liver to peripheral blood (L/P) ratios were higher and averaged 17.5±7.25. It is documented that a C/P ratio of less than (or about) 1.0 and an L/P ratio less than 5 are not indicative of PMR, whereas a C/P ratio exceeding 2 and L/P ratio exceeding 20 highlight a propensity for significant PMR. Our data suggest that DPZ exhibits a moderate degree of PMR. Additionally, a lowered pH was found in all blood specimens (

The yeast mitochondrial Hsp70, Ssc1p, functions as a molecular chaperone with its partner proteins, Mdj1p (DnaJ homologue) and Yge1p (GrpE homologue). We have purified a mature form of Ssc1p from yeast mitochondria and those of Mdj1p and Yge1p from Escherichia coli overexpresser cells. With these purified components of the mitochondrial Hsp70 chaperone system, we have succeeded in reconstituting their chaperone functions in the protection of firefly luciferase against thermal damage in vitro. Heat-denatured luciferase is prevented from irreversible aggregation and is maintained in a refolding-competent state by Ssc1p and/or Mdj1p at 42 degreesC. Luciferase denatured at 42 degreesC is actively reactivated by Ssc1p, Mdj1p and/or Yge1p after lowering the temperature to 25 degreesC. The reactivation process of heat-denatured luciferase shows two-phase kinetics. The slow refolding process requires either Ssc1p or Mdj1p at 42 degreesC but the presence of Ssc1p, Mdj1p and Yge1p, and ATP hydrolysis, is essential at 25 degreesC. The slow refolding of luciferase involves multiple rounds of formation and dissociation of the complex between luciferase and Mdj1p/Ssc1p. On the other hand, the fast refolding process is most enhanced when luciferase is incubated with Ssc1p alone at 42 degreesC, and it requires neither the assistance of Mdj1p and Yge1p nor ATP hydrolysis. We have observed a similar two-pathway reactivation of heat-denatured luciferase by the bacterial Hsp70 and the yeast cytosolic Hsp70 systems.

We report the case of a 51-year-old Japanese woman with a giant (50.75-kg) ovarian tumor. The histopathologic diagnosis was mucinous cystadenocarcinoma. After surgery, the patient was intubated and connected to a respirator for 8 days. Thereafter, she was diagnosed with bone metastasis to the hip bone and the femur.

In this study, the genes expressed in response to low pH stress were identified in the unicellular cyanobacterium Synechocystis sp. PCC 6803 using DNA microarrays. The expression of slr0967 and sll0939 constantly increased throughout 4-h acid stress conditions. Overexpression of these two genes under the control of the trc promoter induced the cells to become tolerant to acid stress. The Δslr0967 and Δsll0939 mutant cells exhibited sensitivity to osmotic and salt stress, whereas the trc mutants of these genes exhibited tolerance to these types of stress. Microarray analysis of the Δslr0967 mutant under acid stress conditions showed that expression of the high light-inducible protein ssr2595 (HliB) and the two-component response regulator slr1214 (rre15) were out of regulation due to gene inactivation, whereas they were upregulated by acid stress in the wild-type cells. Microarray analysis and real-time quantitative reverse transcription-polymerase chain reaction analysis showed that the expression of sll0939 was significantly repressed in the slr0967 deletion mutant. These results suggest that sll0939 is directly involved in the low pH tolerance of Synechocystis sp. PCC 6803 and that slr0967 may be essential for the induction of acid stress-responsive genes.

Two-component signal transduction is the primary signaling mechanism used for global regulation of cell response to changes in the environment. DNA microarray analysis identified genes up-regulated by acid stress in cyanobacteria Synechocystis sp. PCC 6803. Several of these altered genes are thought to be response regulators that are directly involved in this type of stress. Deletion mutants of response regulator genes were constructed and survivability was compared between the cells transfected with mutant and wild-type genes in a low-pH medium. Among these, deletion of slr0081 affected the growth rate under conditions of acid stress (pH 6.0). We examined the genome-wide expression of genes in ΔsIr0081 mutant cells by using DNA microarray in an attempt to determine whether slr0081 is involved in the regulation of other acid stress responsive genes. Our findings by quantitative real-time RT PCR revealed that down regulation of acid responsive genes slr0967 and sll0939 occurs by deletion of slr0081.

Genes expressed in response to low-pH stress in unicellular cyanobacterium Syechosystis sp. PCC 6803 were identified using DNA microarrays. Among these, the expression of slr0967 and sll0939 constantly increased during a 4 h acid stress condition [Photosynth Res. 84:225-30 (2005)]. The growth of the two genes deletion mutants on BG-11 media at pH 6.0 was significantly lower than that of wild-type cells. On the other hand, overexpression of the two genes under the control of the trc promoter caused the cells to become tolerant to shortterm acid stress (pH 3.0 for 8 h). Real-time RT-PCR analysis of these mutants revealed that the expression of sll0939 was significantly repressed in the slr0967 deletion mutant. These results suggest that sll0939 are directly involved in low-pH tolerance of cyanobacrerium Syechosystis sp. PCC6803 and slr0967 may have been essential for induction of acid responsive genes.

The novel rice plant specific kinesin K16 has several unique enzymatic characteristics comparing with conventional kinesin. The most interesting property is that the ADP-free K16 motor domain is very stable, contrast to conventional kinesin that is very labile in ADP-free state. Recently, we have determined crystal structure of the novel rice kinesin K16 motor domain (K16MD) in complex with MgADP at 2.5A resolution. The overall structure of the K16MD is similar to that of conventional kinesin motor domains, as expected from the high similarity of amino acid sequence (43.2 %). However, the neck-linker of the ADP bound K16 motor domain showed an ordered conformation in a position quite different from that observed in conventional kinesin, which may reflect the unique enzymatic characteristics of rice kinesin K16. In the present study, we analyzed the inner structure of the K16 motor domain in detail and compared the structure with Eg5 and other related kinesins. It has been revealed that K16MD does not have interaction of amino acids side chains, which stabilizes the docking conformation of neck-linker. We have also analyzed the conformation of neck-linker in the solution using the K16 by FRET. Motor domain mutant G220C chimera protein fused with GFP at the neck-linker has been prepared and labeled IAE-DANS. The FRET efficiencies between the fluorescent probe DANS at C220 and GFP in the presence and absence of nucleotides were analyzed.

Two-component signal transduction is the primary signaling mechanism for global regulation of the cellular response to environmental changes. We used DNA microarray analysis to identify genes that were upregulated by acid stress in the cyanobacterium Synechocystis sp. PCC 6803. Several of these genes may be response regulators that are directly involved in this type of stress response. We constructed deletion mutants for the response regulator genes and compared the growth rates of cells transfected with mutant and wild-type genes in a low pH medium. Of these mutants, deletion of sphR affected the growth rate under acid stress (pH 6.0) conditions. We examined genome-wide expression in ΔsphR mutant cells using DNA microarray to determine whether SphR was involved in the regulation of other acid stress responsive genes. Microarray and real-time quantitative reverse-transcription polymerase chain reaction (qRT-PCR) analyses of wild-type cells showed that the expression of phoA, pstS1, and pstS2, which are upregulated under phosphate-limiting conditions, increased (2.48-, 1.88-, and 5.07-fold, respectively) after acid stress treatment for 0.5h. In contrast, pstS2 expression did not increase in the ΔsphR mutant cells after acid stress, whereas the phoA and sphX mRNA levels increased. Furthermore, qRT-PCR and northern blot analysis indicated that downregulation of the acid-responsive genes slr0967 and sll0939 occurred with the deletion of sphR. Indeed, mutants of these genes were more sensitive to acid stress than the wild-type cells. Thus, induction of Slr0967 and Sll0939 by SphR may be essential for growth under acid stress conditions. This article is part of a Special Issue entitled: Photosynthesis Research for Sustainability: from Natural to Artificial.