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The use of chemotherapy to manage newly diagnosed low grade glioma (LGG) was first introduced in the 1980s. One randomised trial has studied two- versus four-drug regimens with a duration of 12 months of treatment after resection.Within the European comprehensive treatment strategy for childhood LGG, the International Society of Paediatric Oncology-Low Grade Glioma (SIOP LGG) Committee launched a randomised trial involving 118 institutions and 11 countries to investigate the addition of etoposide (100 mg/mNo differences between the two arms were found in term of survival and radiological response. Response and non-progression rates at 24 weeks for VC and VCE, were 46% versus 41%, and 93% versus 91% respectively; 5-year Progression-Free Survival (PFS) and Overall Survival (OS) were 46% (StDev 3.5) versus 45% (StDev 3.5) and 89% (StDev 2.1) versus 89% (StDev 2.1) respectively. Age and diencephalic syndrome are adverse clinical risk factors for PFS and OS. 5-year OS for patients in early progression at week 24 were 46% (StDev 13.8) and 49% (StDev 16.5) in the two arms, respectively.The addition of etoposide to VC did not improve PFS or OS. High non-progression rates at 24 weeks justify retaining VC as standard first-line therapy. Infants with diencephalic syndrome and early progression need new treatments to be tested. Future trials should use neurological/visual and toxicity outcomes and be designed to discriminate between the impact on disease outcomes of 'duration of therapy' and 'age at stopping therapy'.

Background The use of chemotherapy to manage newly diagnosed low grade glioma (LGG) was first introduced in the 1980s. One randomised trial has studied two- versus four-drug regimens with a duration of 12 months of treatment after resection. Methods Within the European comprehensive treatment strategy for childhood LGG, the International Society of Paediatric Oncology–Low Grade Glioma (SIOP LGG) Committee launched a randomised trial involving 118 institutions and 11 countries to investigate the addition of etoposide (100 mg/m2, days 1, 2 & 3) to a four-course induction of vincristine (1.5 mg/m2 × 10 wkly) and carboplatin (550 mg/m2 q 3 weekly) as part of 18-month continuing treatment programme. Patients were recruited after imaging diagnosis, resection or biopsy with progressive disease/symptoms. Some 497 newly diagnosed patients (M/F 231/266; median age 4.26 years (interquartile range (IQR) 2.02–7.06)) were randomised to receive vincristine carboplatin (VC) (n = 249) or VC plus etoposide (VCE) during induction (n = 248), stratified by age and tumour site. Findings No differences between the two arms were found in term of survival and radiological response. Response and non-progression rates at 24 weeks for VC and VCE, were 46% versus 41%, and 93% versus 91% respectively; 5-year Progression-Free Survival (PFS) and Overall Survival (OS) were 46% (StDev 3.5) versus 45% (StDev 3.5) and 89% (StDev 2.1) versus 89% (StDev 2.1) respectively. Age and diencephalic syndrome are adverse clinical risk factors for PFS and OS. 5-year OS for patients in early progression at week 24 were 46% (StDev 13.8) and 49% (StDev 16.5) in the two arms, respectively. Interpretation The addition of etoposide to VC did not improve PFS or OS. High non-progression rates at 24 weeks justify retaining VC as standard first-line therapy. Infants with diencephalic syndrome and early progression need new treatments to be tested. Future trials should use neurological/visual and toxicity outcomes and be designed to discriminate between the impact on disease outcomes of ‘duration of therapy’ and ‘age at stopping therapy’., Highlights • A randomised trial in the commonest brain tumour type in children – low grade glioma. • Tumour response assessment at 6 months identifies those at greatest risk of subsequent progression and death. • Intensifying induction treatment with etoposide does not improve progression-free survival. • International consortium successfully recruits from 11 European countries in a childhood brain tumour. • Carboplatin hypersensitivity is reduced by coadministration of etoposide.

We have developed a novel real-time quaking-induced conversion RT-QuIC-based assay to detect alpha-synuclein aggregation in brain and cerebrospinal fluid from dementia with Lewy bodies and Parkinson's disease patients. This assay can detect alpha-synuclein aggregation in Dementia with Lewy bodies and Parkinson's disease cerebrospinal fluid with sensitivities of 92% and 95%, respectively, and with an overall specificity of 100% when compared to Alzheimer and control cerebrospinal fluid. Patients with neuropathologically confirmed tauopathies (progressive supranuclear palsy; corticobasal degeneration) gave negative results. These results suggest that RT-QuiC analysis of cerebrospinal fluid is potentially useful for the early clinical assessment of patients with alpha-synucleinopathies.

IMPORTANCE: Whether conservative management is superior to interventional treatment for unruptured brain arteriovenous malformations (bAVMs) is uncertain because of the shortage of long-term comparative data.OBJECTIVE: To compare the long-term outcomes of conservative management vs intervention for unruptured bAVM. DESIGN, SETTING,AND POPULATION: Population-based inception cohort study of 204 residents of Scotland aged 16 years or older who were first diagnosed as having an unruptured bAVM during 1999-2003 or 2006-2010 and followed up prospectively for 12 years.EXPOSURES: Conservative management (no intervention) vs intervention (any endovascular embolization, neurosurgical excision, or stereotactic radiosurgery alone or in combination).MAIN OUTCOMES AND MEASURES: Cox regression analyses, with multivariable adjustment for prognostic factors and baseline imbalances if hazards were proportional, to compare rates of the primary outcome (death or sustained morbidity of any cause by Oxford Handicap Scale [OHS] score ≥2 for ≥2 successive years [0 = no symptoms and 6 = death]) and the secondary outcome (nonfatal symptomatic stroke or death due to bAVM, associated arterial aneurysm, or intervention).RESULTS: Of 204 patients, 103 underwent intervention. Those who underwent intervention were younger, more likely to have presented with seizure, and less likely to have large bAVMs than patients managed conservatively. During a median follow-up of 6.9 years (94% completeness), the rate of progression to the primary outcome was lower with conservative management during the first 4 years of follow-up (36 vs 39 events; 9.5 vs 9.8 per 100 person-years; adjusted hazard ratio, 0.59; 95% CI, 0.35-0.99), but rates were similar thereafter. The rate of the secondary outcome was lower with conservative management during 12 years of follow-up (14 vs 38 events; 1.6 vs 3.3 per 100 person-years; adjusted hazard ratio, 0.37; 95% CI, 0.19-0.72).CONCLUSIONS AND RELEVANCE: Among patients aged 16 years or older diagnosed as having unruptured bAVM, use of conservative management compared with intervention was associated with better clinical outcomes for up to 12 years. Longer follow-up is required to understand whether this association persists.

A proximal myopathy develops in some patients with muscle channelopathies, but the causative molecular mechanisms are unknown.We reviewed retrospectively all clinical and muscle biopsy findings of 3 patients with channelopathy and additional myositis. Direct DNA sequencing was performed.Pathogenic mutations were identified in each case. Biopsies demonstrated inflammatory infiltrates.Clinicians should consider muscle biopsy in channelopathy patients with severe myalgia and/or subacute weakness and accompanying elevated creatine kinase. Chance association of myositis and channelopathy is statistically unlikely. An alternative hypothesis suggests that inflammatory insults could contribute to myopathy in some patients.

Targeted radiopharmaceuticals offer the possibility of improved tumor imaging and radiotherapy, with reduced side effects. A variety of monoclonal antibodies and antibody fragments have previously been successfully radiolabeled and used in diagnostic imaging and targeted radiotherapy of cancer. Many such antibodies have been shown to recognize the well-characterized MUC1 tumor marker and have recently been in clinical trials. Furthermore, a number of chelators have been synthesized and are currently used as radiopharmaceuticals for imaging and therapy. We now report the synthesis of a novel, cyclen-based ligand with a sulfur-containing arm that offers increased stability of the ligand-metal complex. We have coupled this ligand with previously selected aptamers to the MUC1 tumor marker to generate a novel targeted radiopharmaceutical with improved properties. We have tested the complex against known, commercially available chelators such as MAG3 in model breast cancer systems. To improve the pharmacokinetic properties of the aptamer-based targeted radiopharmaceutical, we have generated multi-aptamer complexes around a central chelator. Such multi-aptamer complexes have increased retention of the complex in circulation, without affecting the lack of immunogenicity of the complex or altering its superior tumor penetration properties.

BackgroundSpontaneous intracerebral haemorrhage is a devastating form of stroke and its incidence increases with age. Obtaining brain tissue following intracerebral haemorrhage helps to understand its cause. Given declining autopsy rates worldwide, the feasibility of establishing an autopsy-based collection and its generalisability are uncertain.MethodsWe used multiple overlapping sources of case ascertainment to identify every adult diagnosed with intracerebral haemorrhage between 1st June 2010-31st May 2012, whilst resident in the Lothian region of Scotland. We sought consent from patients with intracerebral haemorrhage (or their nearest relative if the patient lacked mental capacity) to conduct a research autopsy.ResultsOf 295 adults with acute intracerebral haemorrhage, 110 (37%) could not be approached to consider donation. Of 185 adults/relatives approached, 91 (49%) consented to research autopsy. There were no differences in baseline demographic variables or markers of intracerebral haemorrhage severity between consenters and non-consenters. Adults who died and became donors (n = 46) differed from the rest of the cohort (n = 249) by being older (median age 80, IQR 76–86 vs. 75, IQR 65–83, p = 0.002) and having larger haemorrhages (median volume 23ml, IQR 13–50 vs. 13ml, IQR 4–40; p = 0.002).ConclusionsNearly half of those approached consent to brain tissue donation after acute intracerebral haemorrhage. The characteristics of adults who gave consent were comparable to those in an entire community, although those who donate early are older and have larger haemorrhage volumes.

To determine whether in cases of variant Creutzfeldt-Jakob disease (vCJD), the florid-type plaques are derived from the diffuse plaques or whether the 2 plaque types develop independently.Blocks of frontal, parietal, occipital and temporal neocortex and cerebellar cortex from 11 cases of vCJD.The density, distribution and spatial pattern of the florid and diffuse plaques were determined in each brain region using spatial pattern analysis.The density of the diffuse plaques was significantly greater than that of the florid plaques in most areas. The ratio of the diffuse to florid plaques varied between brain regions and was maximal in the molecular layer of the cerebellum. The densities of the florid and diffuse plaques were positively correlated in the parietal cortex, occipital cortex, the inferior temporal gyrus and the dentate gyrus. Plaque densities were not related to disease duration. In the cerebral cortex, the diffuse plaques were more commonly evenly distributed or occurred in large clusters along the cortex parallel to the pia mater compared with the florid plaques which occurred more frequently in regularly distributed clusters.The florid plaques may not be derived from the diffuse plaques, the 2 plaque types appearing to develop independently with unique factors involved in their pathogenesis.

We report a case of gliosarcoma with areas of primitive neuroepithelial differentiation arising in the temporal lobe of a 53-year-old man. The sarcomatous component of this tumor was perivascular in its distribution and showed expression of factor VIII-related antigen, smooth muscle actin and CD34. The primitive neuroepithelial component possessed a small cell morphology and showed expression of neuronal antigens. Strong expression of p53 was demonstrated throughout the tumor with only focal weak expression of epidermal growth factor receptor. The tumor developed widespread extraneural metastases 5 months after surgical resection of the primary tumor. Histological examination of the liver metastases showed them to consist predominantly of the primitive neuroepithelial component. We believe this to be a novel pattern of differentiation in a gliosarcoma which in this case was associated with an aggressive metastatic potential.

In 1996, the CJD surveillance unit in Edinburgh, UK described nvCJD which was thought to be the human equivalent of bovine spongiform encephalopathy (BSE). The identification of prion protein in the tonsil of an affected individual has raised the question of transmission of nvCJD via blood products. This study examines the post mortem brains of 33 patients who were treated with clotting factor concentrate of predominately UK donor source during the years 1962-1995. The brains were examined by conventional histological methods and also for the prion protein using monoclonal antibodies KG9 and 3F4. No evidence of spongiform encephalopathy was found and the immunocytochemistry was negative for PrP in all cases. It is concluded that, at present, there is no evidence for the transmission of nvCJD via clotting factor concentrate to patients with haemophilia.

Following in vitro lipofection transfection of the rat glioma cell line A15A5 with the plasmid transgene CMV/HyTK, which confirms hygromycin resistance and ganciclovir sensitivity, a series of experiments was planned in which the "bystander" phenomenon would be evaluated using the rodent implantation glioma model. However examination of the brain of rodents in which the A15A5HyTK cells were implanted showed no evidence of glioma growth. Furthermore, rodents having intracerebral implantation of (i) wild A15A5 and A15A5HyTK cells in a 50/50 mix, (ii) wild A15A5 and A15A5HyTK cells in a 90/10 mixture and (iii) wild C6 and A15A5HyTK cells in a 50/50 mix all failed to grow macroscopic tumours by 15-17 days irrespective of whether the animals had been administered ganciclovir (GCV) in the week before sacrifice. Neuropathological and immunocytochemical analysis of the implantation sites showed no difference between the GCV and saline treated groups of animals for any implantation cell mix. These observations confirm previous results that suggest transduction of malignant rodent glioma cell lines with a variety of selection, oncogenic and marker genes significantly impairs their in vivo tumorigenic potential compared to the wild type cell lines. This study also demonstrates that even without GCV treatment the transduced cells inhibit, by an unknown mechanism(s), the tumorigenicity of other non transfected malignant cells. The implications of this study for gene therapy of human malignant glioma are discussed.

In a 39-year old woman Creutzfeldt-Jakob disease was diagnosed. More than twenty years prior to the first clinical symptoms she had been treated with human pituitary growth hormone. After four months of illness she died of Creutzfeldt-Jakob disease, as was shown by the post-mortem finding of spongiform encephalopathy immunochemically positive for abnormal prion protein. The patient represented the first case of Creutzfeldt-Jakob disease associated with the use of human growth hormone in the Netherlands.

This study compared a panel of three different prion protein antibodies with conventional plaque staining methods--Congo Red, Periodic acid Schiff and sulphated Alcian blue--to investigate amyloid plaque formation in cases of human spongiform encephalopathy (HSE). Tissue samples were taken from the cerebellum in nine sporadic cases of Creutzfeldt-Jakob Disease, with plaque formation noted on routine histology, and one case of Gerstmann-Straussler Scheinker syndrome. Using image analysis techniques, a semi-automatic system of plaque quantification was devised to measure the relative performance of these different staining methods. A total figure of percentage tissue area stained positively was returned by the system in each case analysed. A significant statistical correlation was observed among all three antibodies (r0.9, P0.01, in all comparisons) and a significant improvement was observed when the average antibody staining figures were compared to those of the Alcian blue technique (P0.05). The distribution of plaques across the cerebellar layers observed here appears to confirm earlier research findings. A strong correlation was found between staining in the two cerebellar hemispheres (r = 0.97, P0.01). This novel image analysis system has considerable potential for objective assessment of the pathology of HSE.

A case of a pituitary adenoma in an acromegalic man is presented in which growth hormone secretion was demonstrated by explant culture. Light microscopy showed the tumor to consist of acidophil "signet ring" cells which contained growth hormone on immunocytochemical studies. Electron microscopy showed a mixed population of densely and sparsely granulated growth hormone adenoma cells. This latter feature has never previously been described, and may represent dual cellular differentiation from an acidophil stem cell precursor.

The surgical management of posterior urethral valves remains controversial. To examine the effects and results of operative treatment in boys with proven posterior urethral valves, a retrospective study was undertaken. The case records of 33 male children who presented with posterior urethral valves over a 10-year period were reviewed. Two patients died prior to definitive treatment and one died postoperatively. Following resuscitation and diagnostic procedures, the remaining patients had eradication of the posterior urethral valves by electrothermic fulguration. In 14 patients this was performed using the Innes-Williams diathermy hook under control of contrast enhanced radiography. In 16 patients the valves were fulgurated under direct cystoscopic visualization. All surviving patients had an uneventful postoperative recovery. However, of those undergoing cystoscopic fulguration, four developed symptomatic urethral strictures necessitating repeat cystoscopy and urethral dilatation. No cases developed strictures following the use of the diathermy hook. One patient from each treatment group developed dribbling. The Innes-Williams diathermy hook has been proven to be a safe, simple, and inexpensive technique. This has specific application in the neonate and small infant where cystoscopy poses technical problems because of anatomic size and where potentially traumatic urethral instrumentation should be avoided.

A man of 61 with a 26-year history of progressive cerebellar ataxia was admitted to hospital. He was found to have chronic liver disease and died 22 days after admission. A diagnosis of hepatolenticular degeneration (Wilson's disease) was supported by clinical investigations and confirmed at autopsy, when tissue copper studies were performed. Several unusual features were present, including a unilateral Kayser-Fleischer ring, a hepatocellular carcinoma, peripheral neuropathy, pontine demyelination and calcification of neurones in the medulla. The significance of these findings is discussed with a review of the relevant literature.

Intracerebral disease was diagnosed in 14 out of 450 patients who presented with non-Hodgkin's lymphoma between January 1976 and January 1987. Twelve of the 14 presented after June 1980. Age ranged from 31 to 73 years and eight patients were male. Two patients had other tumours, and three had relevant associated immunosuppressive disorders. Radiological assessment of one further patient showed a cavitating bronchial carcinoma. Five patients were untreated, and one died before radiotherapy was complete. Eight patients completed courses of whole-brain irradiation; four of these received higher doses. All entered remission. Three patients are alive, between eight months and seven years after treatment. Of the remaining five, one never recovered intellectual function and died of bronchopneumonia; three died between eight and 30 months after treatment and autopsy showed severe radionecrosis of the brain with no residual tumour. All three had received higher doses of radiation and had undergone burrhole aspiration before treatment. Autopsy was refused on one patient who also appeared to have died from radionecrosis of the brain. Immunohistological examination in eight cases confirms that cerebral non-Hodgkin's lymphoma is a B-cell tumour. As other groups have found, its incidence appears to be rising. Survival rate is poor, and at least some deaths are related to both radiation necrosis and the bulk of residual tumour after diagnostic surgery.

We report here the first description of florid plaques--the hallmark of variant Creutzfeldt-Jakob disease (vCJD). These plaques are composed of broad bundles of amyloid, are highly neuritic and exhibited astrocytes and microglial cells. Collectively, they are more similar to neuritic plaques of Alzheimer's disease than to kuru plaques of kuru--Creutzfeldt-Jakob disease--Gerstmann-Sträussler-Sheinker disease.

A recent investigation into prion protein (PrP) deposition in cases of Creutzfeldt-Jakob disease (CJD) has suggested that the spinal cord is affected in some cases of this disease. In an attempt to measure this phenomenon we have used quantitative image analysis techniques to assess the amount of PrP deposited in the spinal cords of three different cases of CJD. By using an automatic method of image intensity threshold setting we have measured the tissue area occupied by PrP in a non-subjective manner. The ranking of these different cases has confirmed that suggested by visual inspection. This analysis shows a substantial variation in the quantity of PrP positivity observed when a panel of different PrP antibodies was compared, confirming early findings. The distribution of PrP across the spinal cord has also been mapped using the image analysis system.

Most neuropathology laboratories have been faced with the question of dealing with cases of Creutzfeldt-Jakob disease (CJD) which is a rare neurodegenerative disorder. Neuropathologists have been long aware of the transmissibility and unique properties of the agent which make it resistant to conventional inactivating reagents. The emergence of iatrogenic cases and of the bovine spongiform encephalopathy (BSE) crisis has induced anxiety among laboratory staff and raised questions about the efficiency of safety measures and procedures hitherto applied in pathology laboratories. This article aims at presenting an overview of the risk involved in handling CJD material. It gives practical advice and a key to more detailed procedures, guidelines and recommendations available in scientific literature and through government agencies. Neuropathologists and biochemists are at a higher potential risk than others since the diagnosing of CJD involves the handling of nervous tissue which contains the highest levels of infectivity.

We reviewed hospital case notes of all incident cases of intracerebral tumours in SE Scotland to analyse referral pattern and time intervals between presentation, diagnosis and treatment. We identified 439 new patients with intracerebral tumours in a two year period: 64% single (primary brain tumours 43%: metastasis 21%) and 36% multiple (metastases). Ninety-two per cent of patients were referred by GP's and 88% were self referrals to hospital or were initially identified at hospital follow-up clinics. Only 27% of patients were initially referred to the specialist centre (Western General Hospital) but 57% were CT scanned at the specialist centre and 83% were referred to there at some time. Time from GP referral to CT scan was related to availability of local CT scanning. Only 10% of cases with probable single metastases and 39% with HGG were treated with surgery plus radiation. Cranial irradiation was started within four weeks of CT diagnosis in 79% of those with metastases but in less than 5% of patients with HGG. The patterns of care for patients with brain tumours show great variation. Hospital referral guidelines, better inter-hospital and inter-department communications and more available access to CT scanning and radiotherapy should improve the quality of care and possibly treatment outcome in this group of patients.

The surgica management of posterior urethral valves remains controversial. To examine the effects and results of operative treatment in boys with proven posterior urethral valves, a retrospective study was undertaken. The case records of 33 male children who presented with posterior urethral valves over a 10-year period were reviewed. Two patients died prior to definitive treatment and one died postoperatively. Following resuscitation and diagnostic procedures, the remaining patients had eradication of the posterior urethral valves by electrothermic fulguration. In 14 patients this was performed using the Innes-Williams diathermy hook under control of contrast enhanced radiography. In 16 patients the valves were fulgurated under direct cystoscopic visualization. All surviving patients had an uneventful postoperative recovery. However, of those undergoing cystoscopic fulguration, four developed symptomatic urethral strictures necessitating repeat cystoscopy and urethral dilatation. No cases developed strictures following the use of the diathermy hook. One patient from each treatment group developed dribbling. The Innes-Williams diathermy hook has been proven to be a safe, simple, and inexpensive technique. This has specific application in the neonate and small infant where cystoscopy poses technical problems because of anatomic size and where potentially traumatic urethral instrumentation should be avoided.