High-dose-rate brachytherapy and hypofractionated external beam radiotherapy combined with long-term hormonal therapy for high-risk and very high-risk prostate cancer: outcomes after 5-year follow-up

The purpose of this study was to report the outcomes of high-dose-rate (HDR) brachytherapy and hypofractionated external beam radiotherapy (EBRT) combined with long-term androgen deprivation therapy (ADT) for National Comprehensive Cancer Network (NCCN) criteria-defined high-risk (HR) and very high-risk (VHR) prostate cancer. Data from 178 HR (n = 96, 54%) and VHR (n = 82, 46%) prostate cancer patients who underwent ¹⁹²Ir-HDR brachytherapy and hypofractionated EBRT with long-term ADT between 2003 and 2008 were retrospectively analyzed. The mean dose to 90% of the planning target volume was 6.3 Gy/fraction of HDR brachytherapy. After five fractions of HDR treatment, EBRT with 10 fractions of 3 Gy was administered. All patients initially underwent ≥6 months of neoadjuvant ADT, and adjuvant ADT was continued for 36 months after EBRT. The median follow-up was 61 months (range, 25–94 months) from the start of radiotherapy. The 5-year biochemical non-evidence of disease, freedom from clinical failure and overall survival rates were 90.6% (HR, 97.8%; VHR, 81.9%), 95.2% (HR, 97.7%; VHR, 92.1%), and 96.9% (HR, 100%; VHR, 93.3%), respectively. The highest Radiation Therapy Oncology Group-defined late genitourinary toxicities were Grade 2 in 7.3% of patients and Grade 3 in 9.6%. The highest late gastrointestinal toxicities were Grade 2 in 2.8% of patients and Grade 3 in 0%. Although the 5-year outcome of this tri-modality approach seems favorable, further follow-up is necessary to validate clinical and survival advantages of this intensive approach compared with the standard EBRT approach.     

Validation of accuracy in image co-registration with computed tomography and magnetic resonance imaging in Gamma Knife radiosurgery

The latest version of Leksell GammaPlan (LGP) is equipped with Digital Imaging and Communication in Medicine (DICOM) image-processing functions including image co-registration. Diagnostic magnetic resonance imaging (MRI) taken prior to Gamma Knife treatment is available for virtual treatment pre-planning. On the treatment day, actual dose planning is completed on stereotactic MRI or computed tomography (CT) (with a frame) after co-registration with the diagnostic MRI and in association with the virtual dose distributions. This study assesses the accuracy of image co-registration in a phantom study and evaluates its usefulness in clinical cases. Images of three kinds of phantoms and 11 patients are evaluated. In the phantom study, co-registration errors of the 3D coordinates were measured in overall stereotactic space and compared between stereotactic CT and diagnostic CT, stereotactic MRI and diagnostic MRI, stereotactic CT and diagnostic MRI, and stereotactic MRI and diagnostic MRI co-registered with stereotactic CT. In the clinical study, target contours were compared between stereotactic MRI and diagnostic MRI co-registered with stereotactic CT. The mean errors of coordinates between images were < 1 mm in all measurement areas in both the phantom and clinical patient studies. The co-registration function implemented in LGP has sufficient geometrical accuracy to assure appropriate dose planning in clinical use.     

SIRPα on CD11c+ cells induces Th17 cell differentiation and subsequent inflammation in the CNS in experimental autoimmune encephalomyelitis

Signal regulatory protein α (SIRPα) is expressed predominantly on type 2 conventional dendritic cells (cDC2s) and macrophages. We previously showed that mice systemically lacking SIRPα were resistant to experimental autoimmune encephalomyelitis (EAE). Here, we showed that deletion of SIRPα in CD11c⁺ cells of mice (Sirpa^ΔDC mice) also markedly ameliorated the development of EAE. The frequency of cDCs and migratory DCs (mDCs), as well as that of Th17 cells, were significantly reduced in draining lymph nodes of Sirpa^ΔDC mice at the onset of EAE. In addition, we found the marked reduction in the number of Th17 cells and DCs in the CNS of Sirpa^ΔDC mice at the peak of EAE. Whereas inducible systemic ablation of SIRPα before the induction of EAE prevented disease development, that after EAE onset did not ameliorate the clinical signs of disease. We also found that EAE development was partially attenuated in mice with CD11c⁺ cell-specific ablation of CD47, a ligand of SIRPα. Collectively, our results suggest that SIRPα expressed on CD11c⁺ cells, such as cDC2s and mDCs, is indispensable for the development of EAE, being required for the priming of self-reactive Th17 cells in the periphery as well as for the inflammation in the CNS.     

OPN4 belongs to the photosensitive system of the human skin

The human skin has previously been described to be affected by light; however, the underlying mechanism remains unknown. OPN4 (melanopsin) expression was first identified in the skin of amphibians; however, whether it is also expressed and functioned in the human skin has not yet been identified. Here, we show that OPN4 was expressed in the human skin tissue and cultures of isolated keratinocytes, melanocytes and fibroblasts. Additionally, Ca²⁺ influx in vitro and ex vivo and phosphorylation of extracellular signal‐regulated kinases 1/2 in human fibroblasts were observed by stimulation of blue light irradiation. Notably, our findings showed that this Ca²⁺ influx and phosphorylation of extracellular signal‐regulated kinases 1/2 are promoted in an intensity‐dependent manner, indicating that the light signal is converted to an intracellular signal via OPN4 in the human skin. Overall, in this study we showed that the human skin functions as a photoreceptor by demonstrating that in human skin, the photoreceptive protein was expressed, and photoreception was conducted via photoreceptive protein.     

Experimental and theoretical study on converting myoglobin into a stable domain-swapped dimer by utilizing a tight hydrogen bond network at the hinge region

Various factors, such as helical propensity and hydrogen bonds, control protein structures. A frequently used model protein, myoglobin (Mb), can perform 3D domain swapping, in which the loop at the hinge region is converted to a helical structure in the dimer. We have previously succeeded in obtaining monomer–dimer equilibrium in the native state by introducing a high α-helical propensity residue, Ala, to the hinge region. In this study, we focused on another factor that governs the protein structure, hydrogen bonding. X-ray crystal structures and thermodynamic studies showed that the myoglobin dimer was stabilized over the monomer when keeping His82 to interact with Lys79 and Asp141 through water moleclues and mutating Leu137, which was located close to the H-bond network at the dimer hinge region, to a hydrophilic amino acid (Glu or Asp). Molecular dynamics simulation studies confirmed that the number of H-bonds increased and the α-helices at the hinge region became more rigid for mutants with a tighter H-bond network, supporting the hypothesis that the myoglobin dimer is stabilized when the H-bond network at the hinge region is enhanced. This demonstrates the importance and utility of hydrogen bonds for designing a protein dimer from its monomer with 3D domain swapping.

The tight H-bond network enhanced the helices at the hinge region and stabilized the myoglobin dimer, providing a unique example of using H-bonds in the design of a dimeric protein through 3D domain swapping.     

Comparison of behavioral and psychological symptoms in early-onset and late-onset Alzheimer's disease

BACKGROUND: When comparing with early-onset Alzheimer's disease (EO-AD) and late-onset Alzheimer's disease (LO-AD), some symptomatological differences in clinical features can be seen between them. Rapid progression, more severe language problems or visuospatial dysfunction occur more often in EO-AD patients. However, there have been very few reports about the differences in behavioral and psychological symptoms between these two groups. AIM: The aim of this study was to demonstrate the differences in behavioral symptoms between EO-AD and LO-AD groups. METHOD: Three hundred and seven consecutive outpatients with AD were put into an EO-AD group (46 patients) or a LO-AD group (261 patients). Comprehensive assessment batteries, including the Neuropsychiatric Inventory (NPI), were administered at the first medical assessment. RESULTS: Significant differences were found between the EO-AD and LO-AD groups in terms of NPI total score (EO-AD: 10.3 +/- 10.9, LO-AD: 17.8 +/- 17.0, p = 0.004) and number of patients who experienced each NPI subscale score (delusion; EO-AD: 13.0%, LO-AD: 50.6%, p < 0.001). There were no differences in cognitive functions or dementia severity between two groups. CONCLUSION: In EO-AD, behavioral and psychological symptoms are relatively fewer than LO-AD at the first medical assessment. Copyright (c) 2007 John Wiley & Sons, Ltd.     

Solitary Fibrous Tumor in the Retroperitoneal Space: Report of a Case

Solitary fibrous tumors (SFTs) are spindle-cell neoplasms originally described in the pleura. It is now known that these tumors can develop in many sites. This report describes the case of a well-circumscribed tumor located around the superior mesenteric artery (SMA), which was initially thought to be either a superior SMA aneurysm, a lymphoma, or a neurogenic tumor. Histological examination demonstrated the tumor to be composed of a cellular proliferation of ovoid to spindle cells with a fine collagenous matrix in the short fascicles. Immunohistochemical staining was strongly positive for CD34 and negative for factor VIII, cytokeratin, desmin, and muscle-specific actin (HHF-35). These findings suggested a diagnosis of SFT in the retroperitoneal space. To our knowledge, this is the first report of an SFT located around the SMA. Based on the above findings, it is important to include SFT in the differential diagnosis of retroperitoneal tumors located around the SMA. Received: August 13, 2001 / Accepted: March 5, 2002 Reprint requests to: M. Kume