COMPARATIVE STUDY ON PERFORMANCE OF VARIOUS ENVIRONMENTAL RADIATION MONITORS.

After the Fukushima Daiichi Nuclear Power Plant accident, the radiation dose for first responders was not evaluated accurately due to lack of the monitoring data. It has been important to evaluate a radiation dose for workers in emergency response at a nuclear accident. In this study, a new device which can evaluate both of external and internal exposure doses was developed and the performance of various environmental radiation monitors including commercially available monitors were tested and compared from the viewpoint of an environmental monitoring at emergency situation. Background counts of the monitors and the ambient dose equivalent rate were measured in Fukushima Prefecture. The detection limit for beta particles was evaluated by the method of ISO11929. The sensitivity for gamma-rays of the dust monitor using a ZnS(Ag) and a plastic scintillator was high, but that of the external exposure monitor using a silicon photodiode with CsI(Tl) crystal was relatively low. The detection limit ranged 190-280 Bq m-3 at 100 µSv h-1, exceeding the detection limit of 100 Bq m-3 in the minimum requirement by the National Regulation Authority in Japan. Use of the shielding with lead is necessary to achieve the minimum requirement. These results indicate that the dust monitor using a ZnS(Ag) scintillator and a plastic scintillator is suitable for the external exposure monitor and the developed internal exposure monitor is for the internal exposure monitor at emergency situation among the evaluated monitors. In the future study, the counting efficiency, the relative uncertainty and the performance of the detection for alpha particles will be evaluated, and it will be considered which type of a monitor is suitable after taking the portability into account.

Tolerance of Vascularized Islet-Kidney Transplants in Rhesus Monkeys.

We previously reported that transplantation (Tx) of prevascularized donor islets as composite islet-kidneys (IK) reversed diabetic hyperglycemia in both miniature swine and baboons. In order to enhance this strategy's potential clinical applicability, we have now combined this approach with hematopoietic stem cell (HSC) Tx in an attempt to induce tolerance in nonhuman primates. IKs were prepared by isolating islets from 70% partial pancreatectomies and injecting them beneath the autologous renal capsule of five rhesus monkey donors at least 3 months before allogeneic IK Tx. HSC Tx was performed after mobilization and leukapheresis of the donors and conditioning of the recipients with total body irradiation, T cell depletion, and cyclosporine. One IK was harvested for histologic analysis and four were transplanted into diabetic recipients. IK Tx was performed either 20-22 (n = 3) or 208 (n = 1) days after HSC Tx. All animals accepted IKs without rejection. All recipients required >20 U/day insulin before IK Tx to maintain <200 mg/dL, whereas after IK Tx, three animals required minimal doses of insulin (1-3 U/day) and one animal was insulin free. These results constitute a proof-of-principle that this IK tolerance strategy may provide a cure for both end-stage renal disease and diabetes without the need for immunosuppression.

Role of Bone Marrow Maturity, Insulin-Like Growth Factor 1 Receptor, and Forkhead Box Protein N1 in Thymic Involution and Rejuvenation.

Thymic involution is associated with age-related changes of the immune system. Utilizing our innovative technique of transplantation of a thymus as an isolated vascularized graft in MHC-inbred miniature swine, we have previously demonstrated that aged thymi are rejuvenated after transplantation into juvenile swine. Here we have studied the role of insulin-like growth factor (IGF) and forkhead-box protein-N1 (FOXN1) as well as bone marrow (BM) in thymic rejuvenation and involution. We examined thymic rejuvenation and involution by means of histology and flow cytometry. Thymic function was assessed by the ability to induce tolerance of allogeneic kidneys. Aged thymi were rejuvenated in a juvenile environment, and successfully induced organ tolerance, while juvenile thymi in aged recipients involuted and had a limited ability to induce tolerance. However, juvenile BM inhibited the involution process of juvenile thymi in aged recipients. An elevated expression of both FOXN1 and IGF1 receptors (IGF-1R) was observed in juvenile thymi and rejuvenated thymi. Juvenile BM plays a role in promoting the local thymic milieu as indicated by its ability to inhibit thymic involution in aged animals. The expression of FOXN1 and IGF-1R was noted to increase under conditions that stimulated rejuvenation, suggesting that these factors are involved in thymic recovery.

New technologies for CAS that might overcome the burden of microembolization.

Microembolization during carotid artery stenting (CAS) is the result of embolic events shown by intraprocedural transcranial Doppler (TCD) or postprocedure diffusion-weighted MRI that do not lead to acute neurological deficit. Although the long term clinical outcome of these silent infarcts is not yet well established, there is increasing evidence that these events could be associated with neurological impairments, such as cognitive decline. In order to prevent microembolization due to excessive catheter manipulation at the time of guiding catheter placement in patients with challenging anatomy, a cervical access system with flow reversal protection was developed. Other embolic events are often seen as the result of plaque protrusion through stent struts. A new type of stent, so-called "hybrid" stent, incorporates the flexibility and conformability of an open-cell stent as well as plaque coverage seen with a close-cell stent, with the goal of achieving better plaque stabilization reducing macro and microembolization, while maintaining original vessel anatomy and flow hemodynamic. At the present time there are three different stents under investigation or this application.

Advantages to Indigo mechanical thrombectomy for ALI: device and technique.

Catheter-directed thrombolysis (CDT) has been used as the first therapeutic option for acute limb ischemia (ALI) due to its less invasive nature; however, recent systematic review showed higher incidence of major complications related to lytic infusion, including hemorrhagic stroke. In this setting, aspiration thrombectomy with Indigo has the greatest advantage of not increasing systemic risk of bleeding. The Indigo™ system from Penumbra® (Alameda, CA, USA) promotes active thrombectomy using a vacuum pump that generates substantial suction, enabling aspiration of clots of varying sizes and lengths. The device has three components: aspiration catheter, separator and pump. There are 2 aspiration catheter sizes: CAT 3 and CAT 5. The separators are intended to mobilize the clot and clean the catheter lumen, and therefore restoring flow for continuous aspiration. The pump is small-sized equipment capable of applying near pure vacuum aspiration pressure of -29 mmHg. Aspiration thrombectomy with Indigo has two key advantages: it does not require the use of lytics, and it provides immediate flow reestablishment. Its use when thrombolysis is contraindicated or has failed is already well established and, in the future, it may likely become the first line endovascular option in patients with acute limb ischemia.

The real impact of telaprevir dosage on the antiviral and side effects of telaprevir, pegylated interferon and ribavirin therapy for chronic hepatitis C patients with HCV genotype 1.

Triple therapy with telaprevir, pegylated interferon and ribavirin has been reported to improve antiviral efficacy but have potentially severe adverse effects in patients with chronic hepatitis C. To avoid the severe effects of telaprevir, lowering the dose has been suggested. However, impact of dosage changes on antiviral and adverse effects remains unclear. One hundred and sixty-six Japanese patients with HCV genotype 1 were treated with triple therapy. The drug exposure of each medication was calculated by averaging the dose actually taken. The overall SVR rate was 82%. The telaprevir discontinuation rate was 26%. The factors associated with discontinuation were an older age (≥65 y.o.) and a higher average dose during treatment. The telaprevir discontinuation rates were 42%, 25% and 14% in patients at ≥35, 25-35 and <25 mg/kg/day of telaprevir and 58% in older patients at ≥35 mg/kg/day of TVR. The factors associated with SVR were treatment-naïve, relapse to previous treatment, higher average telaprevir dose during treatment and completion of treatment. The SVR rate was higher, at 91%, in patients at 25-35 mg/kg/day of telaprevir than the 71% and 78% observed in those at <25 and ≥35 mg/kg/day of drug. In Japanese patients, a mean telaprevir dose of 25-35 mg/kg/day during treatment can augment its efficacy in triple therapy for patients with HCV genotype 1.

Biliary complications in 108 consecutive recipients with duct-to-duct biliary reconstruction in living-donor liver transplantation.

BACKGROUND: Biliary complications remain the leading cause of postoperative complications after living-donor liver transplantation (LDLT) in patients undergoing duct-to-duct choledochocholedochostomy. The aim of this study was to analyze the causes of these complications. METHODS: One hundred eight patients who underwent LDLT with duct-to-duct biliary reconstruction at Mie University Hospital were enrolled in this study. The mean follow-up time was 58.4 months (range, 3-132). The most recent 18 donors underwent indocyanine green (ICG) fluorescence cholangiography for donor hepatectomy. The development of biliary complications was retrospectively analyzed. Biliary complications were defined as needing endoscopic or radiologic treatment. RESULTS: Biliary leakages and strictures occurred in 6 (5.6%) and 15 (13.9%) of the recipients, respectively, and 3 donors (2.7%) experienced biliary leakage. However, since the introduction of ICG fluorescence cholangiography, we have not encountered any biliary complications in either donors or recipients. Biliary leakage was an independent risk factor for the development of biliary stricture (P = .013). Twelve (80%) of the 15 recipients with biliary stricture had successful nonoperative endoscopic or radiologic management, and 3 patients underwent surgical repair with hepaticojejunosotomy. CONCLUSIONS: Biliary leakage was an independent factor for biliary stricture. ICG fluorescence cholangiography might be helpful to reduce biliary complications after LDLT in both donors and recipients.

Risk factors for hepatocellular carcinoma in hepatitis C patients with normal alanine aminotransferase treated with pegylated interferon and ribavirin.

Pegylated interferon (Peg-IFN) plus ribavirin combination therapy is effective in patients with hepatitis C virus (HCV) infection and normal alanine aminotransferase levels (NALT). However, it remains unclear whether the risk of hepatocellular carcinoma (HCC) incidence is actually reduced in virological responders. In this study, HCC incidence was examined for 809 patients with NALT (ALT ≤ 40 IU/mL) treated with Peg-IFN alpha-2b and ribavirin for a mean observation period of 36.2 ± 16.5 months. The risk factors for HCC incidence were analysed by Kaplan-Meier method and Cox proportional hazards model. On multivariate analysis among NALT patients, the risk of HCC incidence was significantly reduced in patients with sustained virological response (SVR) or relapse compared with those showing nonresponse (NR) (SVR vs NR, hazard ratio (HR): 0.16, P = 0.009, relapse vs NR, HR: 0.11, P = 0.037). Other risk factors were older age (≥65 years vs <60 years, HR: 6.0, P = 0.032, 60-64 vs <60 years, HR: 3.2, P = 0.212) and male gender (HR: 3.9, P = 0.031). Among 176 patients with PNALT (ALT ≤ 30 IU/mL), only one patient developed HCC and no significant risk factors associated with HCC development were found. In conclusion, antiviral therapy for NALT patients with HCV infection can lower the HCC incidence in responders, particularly for aged and male patients. The indication of antiviral therapy for PNALT (ALT ≤ 30 IU/mL) patients should be carefully determined.

Preferential expression of cancer/testis genes in cancer stem-like cells: proposal of a novel sub-category, cancer/testis/stem gene.

Cancer/testis (CT) antigens encoded by CT genes are immunogenic antigens, and the expression of CT gene is strictly restricted to only the testis among mature organs. Therefore, CT antigens are promising candidates for cancer immunotherapy. In a previous study, we identified a novel CT antigen, DNAJB8. DNAJB8 was found to be preferentially expressed in cancer stem-like cells (CSCs)/cancer-initiating cells (CICs), and it is thus a novel CSC antigen. In this study, we hypothesized that CT genes are preferentially expressed in CSCs/CICs rather than in non-CSCs/-CICs and we examined the expression of CT genes in CSCs/CICs. The expression of 74 CT genes was evaluated in side population (SP) cells (=CSC) and main population (MP) cells (=non-CSC) derived from LHK2 lung adenocarcinoma cells, SW480 colon adenocarcinoma cells and MCF7 breast adenocarcinoma cells by RT-PCR and real-time PCR. Eighteen genes (MAGEA2, MAGEA3, MAGEA4, MAGEA6, MAGEA12, MAGEB2, GAGE1, GAGE8, SPANXA1, SPANXB1, SPANXC, XAGE2, SPA17, BORIS, PLU-1, SGY-1, TEX15 and CT45A1) showed higher expression levels in SP cells than in MP cells, whereas 10 genes (BAGE1, BAGE2, BAGE4, BAGE5, XAGE1, LIP1, D40, HCA661, TDRD1 and TPTE) showed similar expression levels in SP cells and MP cells. Thus, considerable numbers of CT genes showed preferential expression in CSCs/CICs. We therefore propose a novel sub-category of CT genes in this report: cancer/testis/stem (CTS) genes.

Carotid stenting in asymptomatic patients: how to identify patients without symptoms and at high risk for neurologic events.

During the last 20 years, asymptomatic patients with high-grade carotid stenosis have been treated with carotid endarterectomy and more recently with carotid artery stenting in order to prevent stroke. New, best medical treatment including statins, beta-blockers, antiplatelet therapies, and better diabetes and blood pressure control might reduce the incidence of stroke in this patient population making invasive treatment unnecessary. However, patients with asymptomatic carotid stenosis cannot be considered a homogenous population, and therefore, the therapeutic approach should take into consideration a subgroup of patients with greater risk of cerebrovascular event. Unfortunately, these risk factors are not well categorized thus far, although multiple publications have addressed each one of these factors individually. Recognizing these risk factors is essential for optimizing surveillance and therapeutic approach based on individual risk. The purpose of this article is to review such factors, including patient history, presence of embolic signals on Transcranial Doppler ultrasound, and plaque morphology. These factors should identify high risk asymptomatic individuals who could benefit from carotid stenting or carotid endarterectomy.

Common variant in 6q26-q27 is associated with distal colon cancer in an Asian population.

BACKGROUND AND AIM: Colorectal cancer (CRC) is a multifactorial disease with both environmental and genetic factors contributing to its development. The incidence of CRC is increasing year by year in Japan. Patients with CRC in advanced stages have a poor prognosis, but detection of CRC at earlier stages can improve clinical outcome. Therefore, identification of epidemiologial factors that influence development of CRC would facilitate the prevention or early detection of disease. METHODS: To identify loci associated with CRC risk, we performed a genome-wide association study (GWAS) for CRC and sub-analyses by tumour location using 1583 Japanese CRC cases and 1898 controls. Subsequently, we conducted replication analyses using a total of 4809 CRC cases and 2973 controls including 225 Korean subjects with distal colon cancer and 377 controls. RESULTS: We identified a novel locus on 6q26-q27 region (rs7758229 in SLC22A3, p = 7.92 × 10⁻9, OR of 1.28) that was significantly associated with distal colon cancer. We also replicated the association between CRC and SNPs on 8q24 (rs6983267 and rs7837328, p = 1.51 × 10⁻8 and 7.44 × 10⁻8, ORs of 1.18 and 1.17, respectively). Moreover, we found cumulative effects of three genetic factors (rs7758229, rs6983267, and rs4939827 in SMAD7) and one environmental factor (alcohol drinking) which appear to increase CRC risk approximately twofold. CONCLUSIONS: We found a novel susceptible locus in SLC22A3 that contributes to the risk of distal colon cancer in an Asian population. These findings would further extend our understanding of the role of common genetic variants in the aetiology of CRC.

Combined damage to the right hemispheric hand area in the primary motor and sensory area plays a critical role in motor hemineglect.

Direct evidence of the anatomical localization of brain function is provided by functional neurological changes during awake surgery combined with data from preoperative functional magnetic resonance imaging and diffusion tensor imaging studies. The goal of the present study was to analyze the etiology and mechanism of motor hemineglect using these techniques. Of 29 patients with brain tumors within and near the primary motor area (M1) in whom awake surgery was employed from April 2004 through March 2007, 2 patients evinced motor hemineglect of the left hand during awake surgery. The brain tumors in these 2 cases alone were located just beside the hand area of M1 and the primary sensory area (S1) in the right hemisphere. In case 1, the U fibers that connected the areas activated by hand clenching in M1 with S1 were compressed by the brain tumor. These results suggest that the combination of damage to the right hemispheric hand area in M1 and S1 plays a critical role in the development of motor hemineglect.

Marked and rapid recovery of motor strength in premotor area compared with primary motor area in surgery for brain tumors.

Changes in motor function in response to lesions in the premotor area (PM) and the primary motor area (M1) are difficult to predict. The goal of the present study was to use awake surgery to characterize the functional property of the PM or the M1 in patients with brain tumors. Neurological change before, during and after awake surgery was compared among 8 cases of patients with brain tumors located in the PM or M1. Degree of recovery after awake surgery was better for those with brain tumors in the PM (average motor strength, 2.3) when compared with those with brain tumors in the M1 (average motor strength, 1.0). Mean duration until recovery of motor strength after awake surgery was significantly shorter for those with brain tumors in the PM (4.3 days) when compared with those with brain tumors in the M1 (7.8 days) (p < 0.05). Since the degree of removal of brain tumors was greater in those with tumors in the PM when compared with those with tumors in the M1, and because the size of brain tumors in both areas were comparable, the marked and rapid recovery of motor strength after awake surgery for those with brain tumors in PM was likely related to the specific neurological properties of PM such as the redundant network of the secondary motor area. Recovery of motor strength after awake surgery for those with brain tumors located in PM was relatively marked and rapid when compared with those with brain tumors in the M1.

Damage to the right superior longitudinal fasciculus in the inferior parietal lobe plays a role in spatial neglect.

Functional neurological changes after surgery combined with data from diffusion tensor imaging (DTI) studies can provide direct evidence of anatomical localization of brain function. The goal of the present study was to characterize mechanisms of spatial neglect using these techniques by analyzing two patients with development or worsening of left neglect after surgery at our hospital in 2008. In both cases, the surgical approach was via the right inferior parietal lobes, and damage to the superior longitudinal fasciculus (SLF) was demonstrated after surgery by DTI tractography. By contrast, neither the inferior longitudinal fasciculus (ILF) nor the inferior fronto-occipital fasciculus (IFOF) was damaged. These results suggest that damage to the right SLF in the inferior parietal lobe plays a critical role in the development of spatial neglect.

Precentral knob corresponds to the primary motor and premotor area.

PURPOSE: Cortical mapping during awake surgery assesses intraoperative neurological change in response to electrical stimulation to provide direct information regarding the anatomical localization of the primary motor area (M1). The goal of the present study was to analyze the reliability of the identification of the precentral knob in the axial image of magnetic resonance imaging or functional MRI (fMRI) for the detection of M1. MATERIALS AND METHODS: Among patients with brain tumors within or near M1 in whom awake surgery was employed from April 2004 through March 2007, 14 cases were analyzed in which either the M1 or premotor area (PMA) was successfully detected by mapping during awake surgery. RESULTS: The precentral knob was localized to the PMA in 4 cases and to M1 in 10 cases. By contrast, the gyrus activated by hand clenching in fMRI on the affected side at least partially corresponded to M1 in all cases, while those on the unaffected side corresponded to M1 in 12 of 12 cases. CONCLUSION: These results indicate that the precentral knob corresponds to PMA as well as to M1, whereas the gyrus activated in fMRI corresponds to M1 on the affected and unaffected side.

Assessment of the corona radiata sensory tract using awake surgery and tractography.

Anatomical localization of brain function can be achieved by functional changes during awake surgery combined with tractography constructed by diffusion tensor imaging studies. We aimed to use these techniques to characterize the sensory tract in the corona radiata in patients with closely associated brain tumors. Of nine patients who had brain tumors in the primary sensory area (S1) and who underwent awake surgery between October 2004 and July 2007, two patients showed deterioration in deep sensation during and after awake surgery. Both of these patients also developed involuntary movements (for patient 1 this was myoclonus of the left hand, while patient 2 experienced unintentional lifting of the arm). In these two patients, tumors were located just beside the sensory tract in the corona radiata of the right hemisphere. In patient 2, Wallerian degeneration of the sensory tract and concomitant deterioration of superficial and deep sensation were observed at 6 months after awake surgery. These results suggest that damage to a closely associated sensory tract in the corona radiata is critical to the development of sensory deficits and involuntary movements. For patients who undergo surgical resection of S1 brain tumors, pre-operative tractography to detect the sensory tract in the corona radiata may allow protection of the sensory tract during awake surgery, thereby preventing post-operative sensory deficits.

Functional magnetic resonance imaging is more reliable than somatosensory evoked potential or mapping for the detection of the primary motor cortex in proximity to a tumor.

The accurate localization of the primary motor cortex (M1) is critical for the preservation of motor function during resection of brain tumors in and around the M1. The goal of the present study was to determine which technique provided the most accurate localization of M1. The accuracy of preoperative functional magnetic resonance imaging (fMRI), intraoperative somatosensory evoked potential (SEP) and cortical mapping for the localization of M1 was determined in 17 patients with brain tumors in and around the M1. Because localization of the M1 is typically symmetrical in the cerebral hemispheres, the M1 on the affected side was localized by determination of the M1 location on the unaffected side using fMRI with patient hand clenching. The location of M1 was successfully determined by SEP in 5 of 11 cases. In the remainder of cases, the sulcus at which phase reversal occurred during SEP was shifted 1 or 2 gyri rostral to the central sulcus. The location of M1 was successfully determined by brain mapping in 9 of 15 cases. In the remainder of cases, stimulation failed to elicit a motor response. Finally, the location of M1 was successfully determined by fMRI in 16 of 17 cases. These data indicate that fMRI was more reliable than SEP or brain mapping for the detection of M1 in proximity to a tumor.

Navigation-guided Ommaya reservoir placement: implications for the treatment of leptomeningeal metastases.

Ommaya reservoirs are commonly used in the diagnosis and management of leptomeningeal metastases (LM) from malignant tumors. The present study investigates the utility of an intraoperative navigation-guided technique for Ommaya reservoir placement. Between March 2004 and December 2005, 85 navigation-guided Ommaya reservoir placements were performed in 77 patients with intracranial malignancies at the Komagome Metropolitan Hospital. Anterior horn puncture and posterior horn puncture were used for 59 and 26 procedures, respectively. A slit ventricle was present in 6 cases. All procedures were performed under assistance from the Medtronic STEALTH STATION TRIA navigation system. Computed tomographic (CT) scans were routinely obtained just after completion of the procedure. Patients diagnosed with LM received subsequent treatment. An Ommaya catheter was applied to the ventricular puncture needle registered in the navigation system and was inserted into the lateral ventricle. Using the real-time "Guidance View", the surgeon was able to verify the catheter position continuously during the procedure. Postoperative CT scan revealed an appropriate catheter position in all except for one case. Complications (catheter malposition) occurred in only one case (complication rate, 1.2%). None of the patients experienced hemorrhage or infection. In conclusion, navigation-guided Ommaya reservoir placement was associated with a very low incidence of complications. This method appears to be safe and effective when employed in patients with intracranial malignancy.

Technique and assessment of sentinel lymph node biopsy usefulness in laparoscopy-assisted distal gastrectomy.

BACKGROUND: Recently, some studies have suggested that sentinel node biopsy also can be applied to gastric cancer. The authors apply sentinel lymph node biopsy in laparoscopy assisted distal gastrectomy to perform it as safe limited surgery. Limited surgery is a procedure in which the extent of lesion resection and lymph node dissection is reduced. The authors demonstrate that intraoperative diagnosis of lymph node metastasis is useful in this respect. METHODS: The study was conducted with 38 patients (29 men and 9 women) who had a preoperative diagnosis of T1 tumor invasion. The patients had a mean age of 66.2 years. Patent blue (1%) was injected submucosally into four or five different sites around the primary tumor at 1 ml per site. Blue-stained lymphatics and lymph nodes could be seen by turning over the greater omentum and the lesser omentum extraperitoneally. If blue nodes were found, biopsy was performed. RESULTS: The mean number of blue nodes dissected was 2.5 +/- 1.9. Intraoperative identification and biopsy of blue nodes could be performed for 35 (92.1%) of the 38 patients. Of the 35 patients in whom blue nodes were identified, 4 (9.7%) had metastases in blue nodes confirmed by intraoperative frozen-section diagnosis. Intraoperative frozen-section diagnosis was negative for blue node metastasis in 31 patients. Postoperative permanent section diagnosis also showed no evidence of lymph node metastasis in these 31 patients (100% accuracy, 0% false-negative rates). CONCLUSION: The reported method allows observation of blue-stained lymphatics up to 2 h after patent blue injection. Sentinel node biopsy was performed in laparoscopy assisted distal gastrectomy, making it technically equivalent to open gastrectomy. Sentinel node biopsy can serve as a method to determine the appropriate use of laparoscopy assisted distal gastrectomy for management of T1 gastric cancer.