Therapeutic efficacy of intra-arterial docetaxel and nedaplatin infusion concomitant with radiotherapy for T4 maxillary sinus squamous cell carcinoma.

The aim of this study was to evaluate the efficacy of intra-arterial chemoradiotherapy with docetaxel and nedaplatin for T4 maxillary sinus squamous cell carcinoma (MSSCC). Data were retrospectively analysed for 22 consecutive patients with T4 MSSCC who underwent intra-arterial chemoradiotherapy. Participants received intensity-modulated radiotherapy (70 Gy in 35 fractions) concomitantly with docetaxel (60 mg/m2) and nedaplatin (80 mg/m2) administered every 4 weeks for a total of three sessions. The median follow-up period was 49 months (range 12-91 months). T4a tumours were found in 16 patients (73%) and T4b tumours in six patients (27%). Cervical metastasis was found in nine patients (41%; five N2b, four N2c). The 5-year loco-regional control, disease-free survival, and overall survival rates for patients with T4a disease were 92.3%, 92.3%, and 90.3%, respectively, compared to 83.3% (P = 0.42), 66.7% (P = 0.07), and 83.3% (P = 0.46), respectively, for those with T4b disease. The 5-year loco-regional control, disease-free survival, and overall survival rates for patients with cervical lymph node metastasis were all 87.5% compared to 92.3% (P = 0.86), 84.6% (P = 0.69), and 92.3% (P = 0.93), respectively, for those without cervical metastasis. Intra-arterial chemoradiotherapy with docetaxel and nedaplatin may provide favourable loco-regional control and increased survival in T4 MSSCC.

Occlusal Support, Dysphagia, Malnutrition, and Activities of Daily Living in Aged Individuals Needing Long-Term Care: A Path Analysis.

OBJECTIVES: This study aimed to examine the interrelationships among occlusal support, dysphagia, malnutrition, and activities of daily living in aged individuals needing long-term care. DESIGN: Cross-sectional study and path analysis. SETTING: Long-term health care facilities, acute care hospitals, and the community. PARTICIPANTS: Three hundred and fifty-four individuals aged ≥ 65 years with dysphagia or potential dysphagia in need of long-term care. MEASUREMENTS: The modified Eichner Index, Dysphagia Severity Scale, Mini Nutritional Assessment Short Form, and Barthel index. RESULTS: The participants included 118 males and 236 females with a mean (standard deviation) age of 83 (8) years. A total of 216 participants had functional occlusal support with or without dentures. Of the total participants, 73 were within normal limits regarding the severity of dysphagia, 119 exhibited dysphagia without aspiration, and 162 exhibited dysphagia with aspiration. Only 34 had a normal nutritional status, while 166 participants were malnourished, and 154 were at risk of malnutrition. The median Barthel index score was 30. Path analysis indicated two important findings: occlusal support had a direct effect on dysphagia (standard coefficient = 0.33), and dysphagia was associated directly with malnutrition (standard coefficient = 0.50). Dysphagia and malnutrition were associated directly with impaired activities of daily living (standard coefficient = 0.57, 0.22). CONCLUSION: In aged individuals needing long-term care, occlusal support is associated directly with dysphagia and indirectly with malnutrition and activities of daily living via dysphagia.

Molecular epidemiologic analysis of a Pneumocystis pneumonia outbreak among renal transplant patients.

Between 18 November and 3 December 2011, five renal transplant patients at the Department of Nephrology, Toho University Omori Medical Centre, Tokyo, were diagnosed with Pneumocystis pneumonia (PCP). We used molecular epidemiologic methods to determine whether the patients were infected with the same strain of Pneumocystis jirovecii. DNA extracted from the residual bronchoalveolar lavage fluid from the five outbreak cases and from another 20 cases of PCP between 2007 and 2014 were used for multilocus sequence typing to compare the genetic similarity of the P. jirovecii. DNA base sequencing by the Sanger method showed some regions where two bases overlapped and could not be defined. A next-generation sequencer was used to analyse the types and ratios of these overlapping bases. DNA base sequences of P. jirovecii in the bronchoalveolar lavage fluid from four of the five PCP patients in the 2011 outbreak and from another two renal transplant patients who developed PCP in 2013 were highly homologous. The Sanger method revealed 14 genomic regions where two differing DNA bases overlapped and could not be identified. Analyses of the overlapping bases by a next-generation sequencer revealed that the differing types of base were present in almost identical ratios. There is a strong possibility that the PCP outbreak at the Toho University Omori Medical Centre was caused by the same strain of P. jirovecii. Two different types of base present in some regions may be due to P. jirovecii's being a diploid species.

Affinity imaging mass spectrometry (AIMS): high-throughput screening for specific small molecule interactions with frozen tissue sections.

A novel screening system, using affinity imaging mass spectrometry (AIMS), has been developed to identify protein aggregates or organ structures in unfixed human tissue. Frozen tissue sections are positioned on small (millimetre-scale) stainless steel chips and incubated with an extensive library of small molecules. Candidate molecules showing specific affinity for the tissue section are identified by imaging mass spectrometry (IMS). As an example application, we screened over a thousand compounds against Alzheimer's disease (AD) brain tissue and identified several compounds with high affinity for AD brain sections containing tau deposits compared to age-matched controls. It should also be possible to use AIMS to isolate chemical compounds with affinity for tissue structures or components that have been extensively modified by events such as oxidation, phosphorylation, acetylation, aggregation, racemization or truncation, for example, due to aging. It may also be applicable to biomarker screening programs.

Management of angiogram-negative acute colonic hemorrhage: safety and efficacy of colonoscopy-guided superselective embolization.

BACKGROUND: We evaluated the efficacy and safety of superselective embolization with assistance of colonoscopy for acute colonic hemorrhage. METHODS: Of 92 cases of acute colonic hemorrhage requiring colonoscopic intervention, 11 (12 %) could not be successfully treated. Of these, 10 patients (9 men, mean age 65.5 years, range 39-75 years) underwent superselective embolization. Hemorrhage was caused by diverticular disease (n = 8), polypectomy (n = 1), and vascular malformation (n = 1). In all 10 cases, the radiopaque clips were placed at the bleeding point via colonoscopy. Microcatheters were used in all procedures, and embolization was performed at the level of the vasa recta leading to or near the clips with Gelfoam particles, microcoils, or both. RESULTS: Immediate hemostasis was achieved in all patients. In 6 of 10 patients (60 %), selective angiograms showed no active extravasation at the time of the procedure and the embolization was performed using clips as a landmark. In the remaining four patients, selective angiograms showed active extravasation from the vasa recta leading to the clips. The mean number of embolized vessels with no active extravasation and with active extravasation was 1.83 (range 1-3) and 1.25 (range 1-2), respectively. The mean duration of clinical follow-up was 11.6 months (range 1-29 months). One patient (10 %) bled from a different site than the treated site a month after embolization, but the bleeding ceased after endoscopic intervention. All the patients (100 %) were evaluated for objective evidence of ischemia by colonoscopy. Four of the 10 patients (40 %) were found endoscopically to have small areas of ischemia involving only the mucosa, but they remained asymptomatic. There was no bowel infarction or stricture. CONCLUSIONS: Colonoscopy-assisted superselective embolization may be a safe and useful procedure for acute colonic hemorrhage without active extravasation on angiogram.

Genes associated with the progression of neurofibrillary tangles in Alzheimer's disease.

The spreading of neurofibrillary tangles (NFTs), intraneuronal aggregates of highly phosphorylated microtubule-associated protein tau, across the human brain is correlated with the cognitive severity of Alzheimer's disease (AD). To identify genes relevant to NFT expansion defined by the Braak stage, we conducted whole-genome exon array analysis with an exploratory sample set consisting of 213 human post-mortem brain tissue specimens from the entorinal, temporal and frontal cortices of 71 brain-donor subjects: Braak NFT stages 0 (N=13), I-II (N=20), III-IV (N=19) and V-VI (N=19). We identified eight genes, RELN, PTGS2, MYO5C, TRIL, DCHS2, GRB14, NPAS4 and PHYHD1, associated with the Braak stage. The expression levels of three genes, PHYHD1, MYO5C and GRB14, exhibited reproducible association on real-time quantitative PCR analysis. In another sample set, including control subjects (N=30), and in patients with late-onset AD (N=37), dementia with Lewy bodies (N=17) and Parkinson disease (N=36), the expression levels of two genes, PHYHD1 and MYO5C, were obviously associated with late-onset AD. Protein-protein interaction network analysis with a public database revealed that PHYHD1 interacts with MYO5C via POT1, and PHYHD1 directly interacts with amyloid beta-peptide 42. It is thus likely that functional failure of PHYHD1 and MYO5C could lead to AD development.

Treatment and prognosis of angiosarcoma of the scalp and face: a retrospective analysis of 48 patients.

OBJECTIVE: The objective of this study was to retrospectively analyse the treatment results of clinically localised angiosarcoma of the scalp and face. METHODS: The records of 48 patients who were treated between 1987 and 2009 were reviewed. single modality or a combination of surgery, radiotherapy, chemotherapy and immunotherapy were administered. The median follow-up of all 48 patients was 13.7 months (range 2.5-105.9 months). RESULTS: At the time of analysis, 45 of 48 patients (93.8%) had disease recurrences, and the lung was the most frequent site for recurrence (37 patients). In multivariate analysis, performance status (PS) and number of tumours were significant predictors of lung-metastasis-free (LMF) rate. For patients with multifocal tumours, chemotherapy use significantly decreased the LMF rate (p=0.0072). The 2-year actuarial overall survival (OS), progression-free survival and local control rates in all 48 patients were 22.1%, 10.7% and 46.3%, respectively. In multivariate analysis, PS, number of tumours, surgery and radiotherapy were significant prognostic factors for OS. Patients treated with both surgery and radiotherapy (2-year OS: 45.8%) had a significantly more favourable OS (p<0.0001) than patients treated with either surgery or radiotherapy (2-year OS: 11.1%) and patients treated with neither surgery nor radiotherapy (2-year OS: 0%). CONCLUSIONS: Our results indicated that PS and number of tumours were significant predictors for developing lung metastases. Our results also indicated that PS, number of tumours, surgery use and radiotherapy use were independent prognostic factors for OS. Multimodal treatments including surgery and radiotherapy were effective in improving OS for patients with these tumours. Advances in knowledge Multimodal treatments including surgery and radiotherapy are effective in improving overall survival for patients with angiosarcoma of the scalp and face.

Less protease-resistant PrP in a patient with sporadic CJD treated with intraventricular pentosan polysulphate.

Treatment with intraventricular pentosan polysulphate (PPS) might be beneficial in patients with Creutzfeldt-Jakob disease. We report a 68-year-old woman with sporadic Creutzfeldt-Jakob disease who received continuous intraventricular PPS infusion (1-120 microg/kg/day) for 17 months starting 10 months after the onset of clinical symptoms. Treatment with PPS was well tolerated but was associated with a minor, transient intraventricular hemorrhage and a non-progressive collection of subdural fluid. The patient's overall survival time was well above the mean time expected for the illness but still within the normal range. Post-mortem examination revealed that the level of abnormal protease-resistant prion protein in the brain was markedly decreased compared with levels in brains without PPS treatment. These findings suggest that intraventricular PPS infusion might modify the accumulation of abnormal prion proteins in the brains of patients with sporadic Creutzfeldt-Jakob disease.

Cerebrospinal fluid metabolite and nigrostriatal dopaminergic function in Parkinson's disease.

OBJECTIVES: To evaluate the association between cerebrospinal fluid (CSF) homovanillic acid (HVA) concentrations and nigrostriatal dopaminergic function assessed by positron emission tomography (PET) imaging with carbon-11-labeled 2beta-carbomethoxy-3beta-(4-fluorophenyl)-tropane ((11)C-CFT), which can measure the dopamine transporter (DAT) density, in Parkinson's disease (PD). METHODS: (11)C-CFT PET scans and CSF examinations were performed on 21 patients with PD, and six patients with non-parkinsonian syndromes (NPS) as a control group. RESULTS: In the PD group, CSF HVA concentrations were significantly correlated with the striatal uptake of (11)C-CFT (r = 0.76, P < 0.01). However, in the NPS group, two indices were within the normal range. CONCLUSIONS: In PD, CSF HVA concentrations correlate with nigrostriatal dopaminergic function. Therefore, CSF HVA concentrations may be an additional surrogate marker for estimating the remaining nigrostriatal dopaminergic function in case that DAT imaging is unavailable.

Imaging-pathologic correlation in corticobasal degeneration.

BACKGROUND AND PURPOSE: The clinical diagnosis of corticobasal degeneration (CBD) is often difficult due to varied clinical manifestations. In 4 patients with neuropathologically confirmed CBD, characteristic imaging findings and correlations with neuropathologic features were evaluated. Furthermore, imaging findings in CBD were compared with neuropathologically confirmed progressive supranuclear palsy (PSP) for a differential diagnosis. MATERIALS AND METHODS: Four patients with neuropathologically confirmed CBD were studied. We evaluated the area of the tegmentum in the midsagittal plane, subcortical white matter (SCWM) abnormality, asymmetric cerebral atrophy, and signal-intensity abnormality in the subthalamic nuclei on MR imaging and compared them with histopathologic findings. Then, MR imaging findings in CBD were compared with those in 13 patients with PSP. RESULTS: On MR imaging, 3 patients had asymmetric cerebral atrophy extending to the central sulcus. On midsagittal sections, the mean midbrain tegmentum area was 66 mm(2), being markedly smaller than normal, but there was no significant difference between PSP and CBD. All patients had signal-intensity abnormalities of the SCWM, constituting primary degeneration neuropathologically; however, no diffuse signal-intensity abnormality in the SCWM existed in the 13 patients with PSP. In 3 patients, T1-weighted images showed symmetric high signal intensity in the subthalamic nuclei. Neuropathologically, these areas showed characteristic CBD. MR imaging signal-intensity changes also existed in 4 patients with PSP; however, subthalamic nucleus degeneration was more severe in PSP than in CBD. CONCLUSIONS: In cases with midbrain tegmentum atrophy and signal-intensity changes in the subthalamic nuclei, the differential diagnosis distinguishing CBD from PSP based on MR imaging alone was difficult. White matter lesions and asymmetric atrophy can be useful for a differential diagnosis.

Significance of radio-pathological correlations: differentiating severe central nervous system infection from acute embolic infarction.

We describe two educational autopsy cases of severe central nervous system (CNS) infection and septic emboli, such cases having been difficult to differentiate from acute infarctions via emergency MR imaging studies. We briefly discuss the pathology and MR findings along with radiopathological correlation.

Molecular chaperone-mediated tau protein metabolism counteracts the formation of granular tau oligomers in human brain.

Intracellular accumulation of filamentous tau proteins is a defining feature of neurodegenerative diseases termed tauopathies. The pathogenesis of tauopathies remains largely unknown. Molecular chaperones such as heat shock proteins (HSPs), however, have been implicated in tauopathies as well as in other neurodegenerative diseases characterized by the accumulation of insoluble protein aggregates. To search for in vivo evidence of chaperone-related tau protein metabolism, we analyzed human brains with varying degrees of neurofibrillary tangle (NFT) pathology, as defined by Braak NFT staging. Quantitative analysis of soluble protein levels revealed significant positive correlations between tau and Hsp90, Hsp40, Hsp27, alpha-crystallin, and CHIP. An inverse correlation was observed between the levels of HSPs in each specimen and the levels of granular tau oligomers, the latter of which were isolated from brain as intermediates of tau filaments. We speculate that HSPs function as regulators of soluble tau protein levels, and, once the capacity of this chaperone system is saturated, granular tau oligomers form virtually unabated. This is expressed pathologically as an early sign of NFT formation. The molecular basis of chaperone-mediated protection against neurodegeneration might lead to the development of therapeutics for tauopathies. (c) 2007 Wiley-Liss, Inc.

Interaction of VEGF to gastric low grade MALT lymphoma by Helicobacter heilmannii infection in C57/BL/6 mice.

UNLABELLED: Helicobacter heilmannii (Hh) has been clinically reported to have some relation to gastric low grade MALT lymphoma. Recently, we have formed the gastric MALT lymphoma in C57BL/6 mice. MATERIALS AND METHODS: C57BL/6 mice infected with Hh from cynomolgus monkey for more than 6 months were used. The macroscopic, immunohistochemical and electron microscopic observation was performed RESULTS: MALT lymphoma was formed in almost 100% of the infected mice. Increased VEGF-A and Flt-3 immunoreactivity was recognized. CONCLUSION: Hh was shown to be related to the formation of MALT lymphoma and VEGF is suggested to play a role in this lymphoma.

Phase II trial of radiotherapy after hyperbaric oxygenation with chemotherapy for high-grade gliomas.

We conducted a phase II trial to evaluate the efficacy and toxicity of radiotherapy immediately after hyperbaric oxygenation (HBO) with chemotherapy in adults with high-grade gliomas. Patients with histologically confirmed high-grade gliomas were administered radiotherapy in daily 2 Gy fractions for 5 consecutive days per week up to a total dose of 60 Gy. Each fraction was administered immediately after HBO with the period of time from completion of decompression to irradiation being less than 15 min. Chemotherapy consisted of procarbazine, nimustine (ACNU) and vincristine and was administered during and after radiotherapy. A total of 41 patients (31 patients with glioblastoma and 10 patients with grade 3 gliomas) were enrolled. All 41 patients were able to complete a total radiotherapy dose of 60 Gy immediately after HBO with one course of concurrent chemotherapy. Of 30 assessable patients, 17 (57%) had an objective response including four CR and 13 PR. The median time to progression and the median survival time in glioblastoma patients were 12.3 months and 17.3 months, respectively. On univariate analysis, histologic grade (P=0.0001) and Karnofsky performance status (P=0.036) had a significant impact on survival, and on multivariate analysis, histologic grade alone was a significant prognostic factor for survival (P=0.001). Although grade 4 leukopenia and grade 4 thrombocytopenia occurred in 10 and 7% of all patients, respectively, these were transient with no patients developing neutropenic fever or intracranial haemorrhage. No serious nonhaematological or late toxicities were seen. These results indicated that radiotherapy delivered immediately after HBO with chemotherapy was safe with virtually no late toxicity in patients with high-grade gliomas. Further studies are required to strictly evaluate the effectiveness of radiotherapy after HBO for these tumours.

Comparison of extent of tau pathology in patients with frontotemporal dementia with Parkinsonism linked to chromosome 17 (FTDP-17), frontotemporal lobar degeneration with Pick bodies and early onset Alzheimer's disease.

In order to gain insight into the pathogenesis of frontotemporal lobar degeneration (FTLD), the mean tau load in frontal cortex was compared in 34 patients with frontotemporal dementia linked to chromosome 17 (FTDP-17) with 12 different mutations in the tau gene (MAPT), 11 patients with sporadic FTLD with Pick bodies and 25 patients with early onset Alzheimer's disease (EOAD). Tau load was determined, as percentage of tissue occupied by stained product, by image analysis of immunohistochemically stained sections using the phospho-dependent antibodies AT8, AT100 and AT180. With AT8 and AT180 antibodies, the amount of tau was significantly (P < 0.001 in each instance) less than that in EOAD for both FTDP-17 (8.5% and 10.0% respectively) and sporadic FTLD with Pick bodies (16.1% and 10.0% respectively). With AT100, the amount of tau detected in FTDP-17 was 54% (P < 0.001) of that detected in EOAD, but no tau was detected in sporadic FTLD with Pick bodies using this particular antibody. The amount of insoluble tau deposited within the brain in FTDP-17 did not depend in any systematic way upon where the MAPT mutation was topographically located within the gene, or on the physiological or structural change generated by the mutation, regardless of which anti-tau antibody was used. Not only does the amount of tau deposited in the brain differ between the three disorders, but the pattern of phosphorylation of tau also varies according to disease. These findings raise important questions relating to the role of aggregated tau in neurodegeneration - whether this represents an adaptive response which promotes the survival of neurones, or whether it is a detrimental change that directly, or indirectly, brings about the demize of the affected cell.

Frequent importation of enterovirus 71 from surrounding countries into the local community of Yamagata, Japan, between 1998 and 2003.

Phylogenetic analysis of 45 enterovirus 71 (EV71) isolates for 6 years in Yamagata, Japan, clarified that the annual outbreak of hand-foot-and-mouth disease was due to four genetically distinct subgenogroups, including a novel "B5." Our results suggest that the importation of EV71 from surrounding countries has had a major epidemiological impact on the local community used in our study.

A multidisciplinary treatment strategy that includes high-dose chemotherapy for metastatic retinoblastoma without CNS involvement.

The prognosis of patients with metastatic retinoblastoma is poor with conventional chemotherapy and radiation. Since retinoblastoma is highly chemosensitive, dose-escalation of chemotherapeutic agents with stem cell support should be promising. We report our experience with high-dose chemotherapy (HDC) and autologous stem cell transplantation (SCT) in patients with metastatic retinoblastoma. Five patients with metastatic retinoblastoma underwent HDC with autologous SCT following conventional chemotherapy and local radiation therapy. Stem cells (bone marrow in four and peripheral blood stem cells in one) were collected after marrow involvement was cleared. Melphalan was a key drug in all patients, and was administered in combination with other agents such as cisplatin, cyclophosphamide, carboplatin or thiotepa. Three patients are currently alive disease-free at 113, 107 and 38 months, respectively, from the time of SCT. They had no central nervous system (CNS) involvement. The two patients who died of disease had CNS involvement. No long-term sequelae of HDC have been noted. Our treatment strategy using HDC appears to be effective for treating metastatic retinoblastoma without CNS involvement.

Clinical diagnosis of MM2-type sporadic Creutzfeldt-Jakob disease.

BACKGROUND: No method for the clinical diagnosis of MM2-type sporadic Creutzfeldt-Jakob disease (sCJD) has been established except for pathologic examination. OBJECTIVE: To identify a reliable marker for the clinical diagnosis of MM2-type sCJD. METHODS: CSF, EEG, and neuroimaging studies were performed in eight patients with MM2-type sCJD confirmed by neuropathologic, genetic, and western blot analyses. RESULTS: The eight cases were pathologically classified into the cortical (n = 2), thalamic (n = 5), and combined (corticothalamic) (n = 1) forms. The cortical form was characterized by late-onset, slowly progressive dementia, cortical hyperintensity signals on diffusion-weighted imaging (DWI) of brain, and elevated levels of CSF 14-3-3 protein. The thalamic form showed various neurologic manifestations including dementia, ataxia, and pyramidal and extrapyramidal signs with onset at various ages and relatively long disease duration. Characteristic EEG and MRI abnormalities were almost absent. However, all four patients examined with cerebral blood flow (CBF) study using SPECT showed reduction of the CBF in the thalamus as well as the cerebral cortex. The combined form had features of both the cortical and the thalamic forms, showing cortical hyperintensity signals on DWI and hypometabolism of the thalamus on [18F]2-fluoro-2-deoxy-d-glucose PET. CONCLUSION: For the clinical diagnosis of MM2-type sporadic Creutzfeldt-Jakob disease, cortical hyperintensity signals on diffusion-weighted MRI are useful for the cortical form and thalamic hypoperfusion or hypometabolism on cerebral blood flow SPECT or [18F]2-fluoro-2-deoxy-d-glucose PET for the thalamic form.

Independent accumulations of tau and amyloid beta-protein in the human entorhinal cortex.

BACKGROUND: Previous studies have repeatedly described that neurofibrillary tangles arise earlier than senile plaques (SPs) in the entorhinal cortex, but one study suggested that SPs, if present, enhance the former lesions. All of these studies were performed at the histologic or immunocytochemical level, which may not accurately reflect the actual levels of amyloid beta-protein (Abeta) and tau. OBJECTIVE: To determine whether there is significant interaction between Abeta and tau in the human entorhinal cortex with regard to the Braak stage. METHODS: Biochemical studies were conducted on 50 brains from elderly people, who were mainly at Braak stages I to III. All the cases were examined neuropathologically and staged according to Braak and Braak. A small piece of brain tissue for each case was dissected from the anterior portion of the right entorhinal cortex. The amounts of tau and Abeta in the insoluble fraction of the tissue were quantified using western blotting. RESULTS: The levels of tau and possibly Abeta42 in the entorhinal cortex appeared to rise steeply at approximately age 75. The levels of insoluble tau increased as the Braak stage increased from I to II; however, it had a tendency to remain between stages II and III. The levels of Abeta42 showed a small increase, whereas those of Abeta40 increased continuously as the Braak stage advanced. In contrast, the extent of Abeta42 accumulation increased with increasing Braak stage for SPs. There was no significant correlation between the levels of insoluble tau and Abeta42 in the entorhinal cortex. Even if Abeta did not accumulate to significant extents, substantial accumulation of insoluble tau occurred. CONCLUSION: Accumulations of tau and amyloid beta-protein occur independently in the human entorhinal cortex.