Loss of function of CRT1a (calreticulin) reduces plant susceptibility to Verticillium longisporum in both Arabidopsis thaliana and oilseed rape (Brassica napus).

Brassica napus is highly susceptible towards Verticillium longisporum (Vl43) with no effective genetic resistance. It is believed that the fungus reprogrammes plant physiological processes by up-regulation of so-called susceptibility factors to establish a compatible interaction. By transcriptome analysis, we identified genes, which were activated/up-regulated in rapeseed after Vl43 infection. To test whether one of these genes is functionally involved in the infection process and loss of function would lead to decreased susceptibility, we firstly challenged KO lines of corresponding Arabidopsis orthologs with Vl43 and compared them with wild-type plants. Here, we report that the KO of AtCRT1a results in drastically reduced susceptibility of plants to Vl43. To prove crt1a mutation also decreases susceptibility in B. napus, we identified 10 mutations in a TILLING population. Three T3 mutants displayed increased resistance as compared to the wild type. To validate the results, we generated CRISPR/Cas-induced BnCRT1a mutants, challenged T2 plants with Vl43 and observed an overall reduced susceptibility in 3 out of 4 independent lines. Genotyping by allele-specific sequencing suggests a major effect of mutations in the CRT1a A-genome copy, while the C-genome copy appears to have no significant impact on plant susceptibility when challenged with Vl43. As revealed by transcript analysis, the loss of function of CRT1a results in activation of the ethylene signalling pathway, which may contribute to reduced susceptibility. Furthermore, this study demonstrates a novel strategy with great potential to improve plant disease resistance.

Suppression of abscisic acid biosynthesis at the early infection stage of Verticillium longisporum in oilseed rape (Brassica napus).

Verticillium longisporum infects oilseed rape (Brassica napus) and Arabidopsis thaliana. To investigate the early response of oilseed rape to the fungal infection, we determined transcriptomic changes in oilseed rape roots at 6 days post-inoculation (dpi) by RNA-Seq analysis, in which non-infected roots served as a control. Strikingly, a subset of genes involved in abscisic acid (ABA) biosynthesis was found to be down-regulated and the ABA level was accordingly attenuated in 6 dpi oilseed rape as compared with the control. Gene expression analysis revealed that this was mainly attributed to the suppression of BnNCED3-mediated ABA biosynthesis, involving, for example, BnWRKY57. However, this down-regulation of ABA biosynthesis could not be observed in infected Arabidopsis roots. Arabidopsis ABA- defective mutants nced3 and aao3 displayed pronounced tolerance to the fungal infection with delayed and impeded symptom development, even though fungal colonization was not affected in both mutants. These data suggest that ABA appears to be required for full susceptibility of Arabidopsis to the fungal infection. Furthermore, we found that in both 6 dpi oilseed rape and the Arabidopsis nced3 mutant, the salicylic acid (SA) signalling pathway was induced while the jasmonic acid (JA)/ethylene (ET) signalling pathway was concomitantly mitigated. Following these data, we conclude that in oilseed rape the V. longisporum infection triggers a host-specific suppression of the NCED3-mediated ABA biosynthesis, consequently increasing plant tolerance to the fungal infection. We believe that this might be part of the virulence strategy of V. longisporum to initiate/establish a long-lasting compatible interaction with oilseed rape (coexistence), which appears to be different from the infection process in Arabidopsis.

[Interdisciplinary Management of Sellar Masses]. / Interdisziplinäres Management von Hypophysentumoren.

Interdisciplinary Management of Sellar Masses Abstract. Sellar masses may present with an impairment of pituitary function (hypopituitarism), hormone hypersecretion (prolactinoma, acromegaly, glucocorticoid excess) or neurological symptoms (visual impairment, headache). An increasing number of them is discovered as an incidentaloma. Among the various entities, benign pituitary adenomas and cystic lesions are most frequently encountered. The work-up includes a laboratory evaluation for hormone hyper- or hyposecretion and an MRI of the pituitary gland. If the optic chiasm is compromised, a visual field examination is mandatory. Except for prolactinomas, symptomatic sellar masses are usually resected via an endoscopic transsphenoidal approach. If a total resection is not feasible because of the invasion of surrounding structures, debulking to relieve pressure from the optic chiasm is the primary goal and radiotherapy may be considered. Residual hormone excess can be treated medically. In the early postoperative period special attention to the development and treatment of disordered body water homeostasis and hypopituitarism is crucial. Interdisciplinary work-up and decision making are of utmost importance and will offer the best management.

High-dose chemotherapy with autologous haemopoietic stem cell transplantation for newly diagnosed primary CNS lymphoma: a prospective, single-arm, phase 2 trial.

BACKGROUND: High-dose methotrexate-based chemotherapy is standard for primary CNS lymphoma, but most patients relapse. High-dose chemotherapy with autologous stem cell transplantation (HCT-ASCT) is supposed to overcome the blood-brain barrier and eliminate residual disease in the CNS. We aimed to investigate the safety and efficacy of HCT-ASCT in patients with newly diagnosed primary CNS lymphoma. METHODS: In this prospective, single-arm, phase 2 trial, we recruited patients aged 18-65 years with newly diagnosed primary CNS lymphoma and immunocompetence, with no limitation on clinical performance status, from 15 hospitals in Germany. Patients received five courses of intravenous rituximab 375 mg/m(2) (7 days before first high-dose methotrexate course and then every 10 days) and four courses of intravenous high-dose methotrexate 8000 mg/m(2) (every 10 days) and then two courses of intravenous rituximab 375 mg/m(2) (day 1), cytarabine 3 g/m(2) (days 2 and 3), and thiotepa 40 mg/m(2) (day 3). 3 weeks after the last course, patients commenced intravenous HCT-ASCT (rituximab 375 mg/m(2) [day 1], carmustine 400 mg/m(2) [day 2], thiotepa 2 × 5 mg/kg [days 3 and 4], and infusion of stem cells [day 7]), irrespective of response status after induction. We restricted radiotherapy to patients without complete response after HCT-ASCT. The primary endpoint was complete response at day 30 after HCT-ASCT in all registered eligible patients who received at least 1 day of study treatment. This trial is registered at ClinicalTrials.gov, number NCT00647049. FINDINGS: Between Jan 18, 2007, and May 23, 2011, we recruited 81 patients, of whom two (2%) were excluded, therefore we included 79 (98%) patients in the analysis. All patients started induction treatment; 73 (92%) commenced HCT-ASCT. 61 (77·2% [95% CI 66·1-86·6]) patients achieved a complete response. During induction treatment, the most common grade 3 toxicity was anaemia (37 [47%]) and the most common grade 4 toxicity was thrombocytopenia (50 [63%]). During HCT-ASCT, the most common grade 3 toxicity was fever (50 [68%] of 73) and the most common grade 4 toxicity was leucopenia (68 [93%] of 73). We recorded four (5%) treatment-related deaths (three [4%] during induction and one [1%] 4 weeks after HCT-ASCT). INTERPRETATION: HCT-ASCT with thiotepa and carmustine is an effective treatment option in young patients with newly diagnosed primary CNS lymphoma, but further comparative studies are needed. FUNDING: University Hospital Freiburg and Amgen.

Rapid Intracranial Response to Osimertinib in a Patient with Epidermal Growth Factor Receptor T790M-Positive Adenocarcinoma of the Lung.

BACKGROUND: Osimertinib (AZD9291, Tagrisso) is a potent, irreversible third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI). CASE REPORT: Our report demonstrates that osimertinib is able to inhibit the growth of a radiotherapy- and surgery-refractory EGFR T790M-positive brain metastasis in a patient with lung adenocarcinoma. CONCLUSION: These data show that re-biopsy in EGFR-mutated non-small cell lung cancer patients with acquired TKI resistance should be performed.

[Meningioma: management of the most common brain tumour]. / Das Meningeom: Management des häufigsten hirneigenen Tumors.

Meningiomas are the most common primary brain tumours in adults and are therefore relevant for general practitioners. Most meningiomas are benign and neurosurgical resection offers the best chance of cure. However, complete resection is not achievable in many patients. This accounts for a relevant rate of tumour recurrences within 15 years of follow up. In atypical and anaplastic meningiomas of WHO grade II and III time to recurrence is dramatically shorter and these tumours need multimodal treatment strategies including postoperative radiotherapy. Various systemic treatments have occasionally been used as salvage therapy, but were essentially not effective. Only recently, Sunitinib, a small thyrosine kinase inhibitor as well as bevacizumab, a therapeutic antibody, have shown more promising results in highly pretreated, refractory meningioma patients.

Multicenter clinical experience in over 125 patients with the Penumbra Separator 3D for mechanical thrombectomy in acute ischemic stroke.

BACKGROUND: The aim of this study was to assess reperfusion and clinical outcome of treatment with the self-expanding retrievable Separator 3D in revascularization of acute ischemic stroke. The three-dimensional (3D) device secures thrombus with direct aspiration and supports debulking of the clot. METHODS: At two centers, 129 consecutive stroke patients with National Institutes of Health Stroke Scale (NIHSS) scores ≥5 were treated with mechanical thrombectomy using the Separator 3D as a component of the Penumbra System within 8 h of symptom onset; modified Treatment in Cerebral Infarction (mTICI) revascularization scores, NIHSS score on admission and discharge, mortality rates, and modified Rankin Scale (mRS) outcomes at 90 days were evaluated. RESULTS: A total of 129 vessels in 129 patients were treated. Occlusions were located in the middle cerebral artery (MCA, 48%), internal carotid artery (ICA, 33%), cervical ICA-MCA (3%), and vertebrobasilar arteries (16%). Intravenous thrombolytic therapy with recombinant tissue plasminogen activator was given to 78% of patients. Median NIHSS was 15 prior to treatment. Reperfusion to mTICI 2b or 3 was successful in 96/129 (74%) target arterial lesions, with more than half of cases (51%) achieving mTICI 3. The mean time from arterial puncture to revascularization was 65 min. At 90 days, the symptomatic intracranial hemorrhage rate was 4%, all cause mortality was 32%, and 43/99 patients (43%) achieved functional independence with an mRS score of ≤2. CONCLUSIONS: The results suggest that the Separator 3D enables safe and effective revascularization of occluded large arteries in acute stroke intervention, leading to a high rate of functional independence at 90 days.

Characterization of endolymphatic sac tumors and von Hippel-Lindau disease in the International Endolymphatic Sac Tumor Registry.

BACKGROUND: Endolymphatic sac tumors (ELSTs) are, with a prevalence of up to 16%, a component of von Hippel-Lindau (VHL) disease. Data from international registries regarding heritable fraction and characteristics, germline VHL mutation frequency, and prevalence are lacking. METHODS: Systematic registration of ELSTs from international centers of otorhinolaryngology and from multidisciplinary VHL centers' registries was performed. Molecular genetic analyses of the VHL gene were offered to all patients. RESULTS: Our population-based registry comprised 93 patients with ELST and 1789 patients with VHL. The prevalence of VHL germline mutations in apparently sporadic ELSTs was 39%. The prevalence of ELSTs in patients with VHL was 3.6%. ELST was the initial manifestation in 32% of patients with VHL-ELST. CONCLUSION: Prevalence of ELST in VHL disease is much lower compared to the literature. VHL-associated ELSTs can be the first presentation of the syndrome and mimic sporadic tumors, thus emphasizing the need of molecular testing in all presentations of ELST. © 2015 Wiley Periodicals, Inc. Head Neck 38: 673-679, 2016.

Dural arteriovenous fistulas of the hypoglossal canal: systematic review on imaging anatomy, clinical findings, and endovascular management.

Dural arteriovenous fistulas (DAVFs) of the hypoglossal canal (HCDAVFs) are rare and display a complex angiographic anatomy. Hitherto, they have been referred to as various entities (for example, "marginal sinus DAVFs") solely described in case reports or small series. In this in-depth review of HCDAVF, the authors describe clinical and imaging findings, as well as treatment strategies and subsequent outcomes, based on a systematic literature review supplemented by their own cases (120 cases total). Further, the involved craniocervical venous anatomy with variable venous anastomoses is summarized. Hypoglossal canal DAVFs consist of a fistulous pouch involving the anterior condylar confluence and/or anterior condylar vein with a variable intraosseous component. Three major types of venous drainage are associated with distinct clinical patterns: Type 1, with anterograde drainage (62.5%), mostly presents with pulsatile tinnitus; Type 2, with retrograde drainage to the cavernous sinus and/or orbital veins (23.3%), is associated with ocular symptoms and may mimic cavernous sinus DAVF; and Type 3, with cortical and/or perimedullary drainage (14.2%), presents with either hemorrhage or cervical myelopathy. For Types 1 and 2 HCDAVF, transvenous embolization demonstrates high safety and efficacy (2.9% morbidity, 92.7% total occlusion). Understanding the complex venous anatomy is crucial for planning alternative approaches if standard transjugular access is impossible. Transarterial embolization or surgical disconnection (morbidity 13.3%-16.7%) should be reserved for Type 3 HCDAVFs or lesions with poor venous access. A conservative strategy could be appropriate in Type 1 HCDAVF for which spontaneous regression (5.8%) may be observed.

Management of von hippel-lindau disease: an interdisciplinary review.

Von Hippel-Lindau (VHL) disease is an autosomal dominantly inherited tumour predisposition syndrome with an incidence of 1:36,000 newborns, the estimated prevalence in Europe is about 1-9/100,000. It is associated with an increased risk of developing various benign and malignant tumours, thus affecting multiple organs at different time points in the life of a patient. Disease severity and diversity as well as age at first symptoms vary considerably, and diagnostic delay due to failure of recognition is a relevant issue. The identification of a disease-causing VHL germline mutation subsequently allows family members at risk to undergo predictive genetic testing after genetic counselling. Clinical management of patients and families should optimally be offered as an interdisciplinary approach. Prophylactic screening programs are a cornerstone of care, and have markedly improved median overall survival of affected patients. The aim of this review is to give an overview of the heterogeneous manifestations of the VHL syndrome and to highlight the diagnostic and therapeutic challenges characteristic for this orphan disease. A comprehensive update of the underlying genetic and molecular principles is additionally provided. We also describe how the St. Gallen VHL multidisciplinary group is organised as an example of interdisciplinary cooperation in a tertiary hospital in Switzerland.

Vertebral artery dissection associated with sildenafil abuse.

We present a 49-year-old male who suffered a cerebellar infarction due to a vertebral artery dissection. The patient had taken sildenafil daily for at least 2 years for sexual enhancement. There was no sexual intercourse or traumatic event prior to symptom onset. Sildenafil intake has been associated with aortic dissection and, in the light of this report, we suggest that chronic sildenafil intake could be a risk factor for arterial dissection.

18F-FDG PET is an independent outcome predictor in primary central nervous system lymphoma.

UNLABELLED: Primary central nervous system (CNS) lymphoma is an aggressive non-Hodgkin lymphoma with poor prognosis. We evaluated pretreatment (18)F-FDG PET as a prognostic marker in primary CNS lymphoma. METHODS: Forty-two immunocompetent patients with newly diagnosed primary CNS lymphoma who underwent pretreatment (18)F-FDG PET were retrospectively analyzed. Baseline status and response to treatment were evaluated by MR imaging. Tumor maximum standardized uptake values were assessed by volume-of-interest analyses using an automatic isocontour definition. A 10-step semiquantitative visual rating system (metabolic imaging lymphoma aggressiveness scale, or MILAS) was used to assess primary CNS lymphoma metabolism as a marker of clinical aggressiveness. Logistic regression, log-rank testing, and multivariable Cox regression were used to investigate the association between (18)F-FDG uptake and tumor response and survival. RESULTS: Mean maximum standardized uptake value correlated linearly with MILAS. The distribution of patients according to MILAS (0-9) was 0%, 28.6%, 23.8%, 21.4%, 11.9%, 4.8%, 7.1%, 0%, 0%, and 2.4%. There was no correlation between MILAS and response to treatment. Respective 2- and 5-y survival rates were 52% and 32% for progression-free survival (PFS) and 64% and 50% for overall survival (OS). A cutoff at MILAS 3 was a good separator for PFS (median: 54.7 mo [≤3], 3.8 mo [>3], P = 0.0272) and OS (median: not reached [≤3], 13.8 mo [>3], P = 0.131). In multivariable analyses, increasing MILAS was significantly associated with shorter PFS (hazard ratio, 1.49, P = 0.006) and OS (hazard ratio, 1.43, P = 0.018). CONCLUSION: Increased pretreatment (18)F-FDG uptake may offer new opportunities for baseline risk evaluation in untreated primary CNS lymphoma.

Who needs a Wada test? Present clinical indications for amobarbital procedures.

INTRODUCTION: The Wada test has been the gold standard for testing cerebral language localisation during presurgical investigation in the past decades. However, during the last few years a shift has occurred in epilepsy surgery programmes towards the use of non-invasive methods, predominantly functional MRI (fMRI). However, Wada tests are still performed, albeit in a considerably smaller number of patients at many epilepsy centres. METHODS: A retrospective monocentric analysis of remaining clinical indications for performing a Wada procedure was undertaken. The clinical data of patients who participated in Wada tests (42 hemispheric and 8 superselective procedures) during recent years were retrospectively evaluated. RESULTS: Reasons for conducting a Wada test were (1) a patient's inability to perform the fMRI task due to agitation, mental disablement, or perceptual impairment, (2) validation of atypical, inconclusive or not clearly lateralised language activation shown with fMRI, (3) evaluation of propagation of ongoing interictal bilateral epileptiform EEG activity, (4) region selective testing of language and other cognitive functions, or (5) assessment of motor localisation. Patients who were not able to perform the fMRI task or in whom fMRI did not provide interpretable results were significantly younger (p<0.05). CONCLUSION: It is argued that fMRI is eligible to replace Wada tests in the majority of patients who are compliant with clearly lateralised language localisation, but in patients who are agitated or mentally impaired as well as in the case of the above-mentioned specific clinical indications and bilateral fMRI activations, Wada tests still provide additional information. Additionally, non-invasive methods less sensitive to movement artefacts are discussed as possible alternatives for these patients.

Brainstem compression caused by bilateral traumatic carotid cavernous fistulas: case report.

BACKGROUND: Bilateral traumatic carotid cavernous fistulas (CCFs) are rare and may dilate the cavernous sinus. We present a case of brainstem compression caused by a cavernous sinus dilated by the arterial pressure of bilateral CCF. CLINICAL PRESENTATION: A 30-year-old man suffered severe head trauma in a motorbike accident. Hemodynamically relevant, untreatable epistaxis required angiography, which revealed acute bleeding of the left sphenopalatine artery and bilateral traumatic CCFs. The bleeding was stopped by embolization with particles, and the left CCF was partially embolized to stabilize the patient hemodynamically. After short-term treatment and a long clinical course, the patient was referred to rehabilitation. Three months after trauma, the patient presented with severe headache and a dilated right pupil; he was somnolent. Immediate cerebral computed tomography scan showed a retroclival mass compressing the brainstem. Digital subtraction angiography revealed a reperfused left-sided CCF causing a huge dilatation of the retroclival cavernous sinus. After embolization with 2 balloons, the symptoms resolved and the patient was readmitted to rehabilitation. CONCLUSION: Bilateral traumatic CCFs are uncommon. Brainstem impairment caused by venous congestion and consecutive edema is an extremely rare complication of CCFs, with only a few cases reported in the literature. Direct compression of the brainstem by CCFs has, to the best of our knowledge, never been reported before. Immediate endovascular intervention led to complete remission of the symptoms.

[Hemorrhage after embolization of a cerebral AVM]. / Blutung nach Embolisation einer zerebralen AVM.

The report concerns a 36-year-old patient with left temporal arteriovenous malformation (AVM). After interdisciplinary consultation, combined treatment with endovascular embolization and subsequent stereotactic irradiation was recommended. 2 h following embolization, which was complication-free, there was left temporal bleeding with ventricular tamponade. Once the patient had survived the acute phase with application of external drainage and later implantation of a shunt system, he was left with an organic brain syndrome. His lawyer brought suit against the clinic for improper treatment and inadequate information. The court rejected the suit as without foundation, basing its reasoning essentially on the statements of the neuroradiologic expert.

Multi-focal occurrence of cortical dysplasia in epilepsy patients.

This study describes the existence and the clinical and electrophysiological features of multi-focal cortical dysplasia in epilepsy patients. Five patients with intractable focal epilepsy are reported. All patients underwent invasive presurgical video-electroencephalography monitoring. Localization of dysplastic areas was based on high-resolution magnetic resonance scanning, surface and intracranial electroencephalography. Four patients underwent epilepsy surgery. Histological findings in focal cortical dysplasia (FCD) were classified according to Palmini. In addition, genetic examinations were performed in order to assess possible mutations in the genes for tuberous sclerosis complex. In four patients, FCDs were located in the same hemisphere. One case presented with bilateral FCDs. In three patients seizures arose from two separate dysplastic areas and in one patient, one lesion showed only interictal activity. In one further patient, seizures started exclusively from the hippocampus. In two of three patients with removal of the FCDs, the histological subtype was identical (Palmini type 2) and in one patient, histology differed between the lesions. All operated patients became seizure-free. In patients with FCD type 2, germ-line mutations in the tuberous sclerosis complex genes were not detectable. Dysplastic brain regions may not be restricted to a single brain region. Areas of FCD can have different degrees of epileptogenicity, ranging from electrographic silence to interictal epileptic discharges and initial involvement in seizure generation. Based on genetic analysis and clinical features, multi-FCD in this patient series was not likely to be related to tuberous sclerosis.