Suspected tick-borne flavivirus meningoencephalomyelitis in dogs from the UK: six cases (2021).

OBJECTIVES: Tick-borne encephalitis virus and louping ill virus are neurotropic flaviviruses transmitted by ticks. Epidemiologically, tick-borne encephalitis is endemic in Europe whereas louping ill's predominant geographical distribution is the UK. Rarely, these flaviviruses affect dogs causing neurological signs. This case series aimed to describe the clinical, clinicopathological, and imaging findings, as well as the outcomes in six dogs with meningoencephalitis and/or meningomyelitis caused by a flavivirus in the UK in 2021. MATERIALS AND METHODS: Observational retrospective case-series study. Clinical data were retrieved from medical records of dogs with positive serological or immunohistochemical results from three different institutions from spring to winter 2021. RESULTS: Six dogs were included in the study. All dogs presented an initial phase of pyrexia and/or lethargy followed by progressive signs of spinal cord and/or intracranial disease. Magnetic resonance imaging showed bilateral and symmetrical lesions affecting the grey matter of the thalamus, pons, medulla oblongata, and thoracic or lumbar intumescences with none or mild parenchymal and meningeal contrast enhancement. Serology for tick-borne encephalitis virus was positive in five dogs with the presence of seroconversion in two dogs. The viral distinction between flaviviruses was not achieved. One dog with negative serology presented positive immunohistochemistry at post-mortem examination. Three dogs survived but presented neurological sequelae. Three dogs were euthanased due to the rapid progression of the clinical signs or static neurological signs. CLINICAL SIGNIFICANCE: These cases raise awareness of the presence of tick-borne encephalitis as an emergent disease or the increased prevalence of louping ill virus affecting dogs in the UK.

Rift Valley fever virus detection in susceptible hosts with special emphasis in insects.

Rift Valley fever phlebovirus (RVFV, Phenuiviridae) is an emerging arbovirus that can cause potentially fatal disease in many host species including ruminants and humans. Thus, tools to detect this pathogen within tissue samples from routine diagnostic investigations or for research purposes are of major interest. This study compares the immunohistological usefulness of several mono- and polyclonal antibodies against RVFV epitopes in tissue samples derived from natural hosts of epidemiologic importance (sheep), potentially virus transmitting insect species (Culex quinquefasciatus, Aedes aegypti) as well as scientific infection models (mouse, Drosophila melanogaster, C6/36 cell pellet). While the nucleoprotein was the epitope most prominently detected in mammal and mosquito tissue samples, fruit fly tissues showed expression of glycoproteins only. Antibodies against non-structural proteins exhibited single cell reactions in salivary glands of mosquitoes and the C6/36 cell pellet. However, as single antibodies exhibited a cross reactivity of varying degree in non-infected specimens, a careful interpretation of positive reactions and consideration of adequate controls remains of critical importance. The results suggest that primary antibodies directed against viral nucleoproteins and glycoproteins can facilitate RVFV detection in mammals and insects, respectively, and therefore will allow RVFV detection for diagnostic and research purposes.

Decoding Ferenczi's clinical diary: biographical notes.

In the Clinical Diary of Sándor Ferenczi, certain codes and abbreviations are used to refer to the eight patients Ferenczi was treating in 1932. The identities of two patients are known to us. Notably, Dm. (Clara Thompson), and R.N. (Elizabeth Severn), but the others have remained a mystery. This paper uncovers the identities of the other patients in the Diary, and, for the first time, reveals their identities and life stories. Biographical notes on these patients are provided to expand and contextualize our understanding of their lives-Who were they? What kind of families did they come from? And what happened to them after their analyses? The process of uncovering their identities and the ethics of writing about historical patients will also be addressed.

Synovial sarcoma in children and adolescents: the European Pediatric Soft Tissue Sarcoma Study Group prospective trial (EpSSG NRSTS 2005).

BACKGROUND: To report the results of the first European prospective nonrandomized trial dedicated to pediatric synovial sarcoma. PATIENTS AND METHODS: From August 2005 to August 2012, 138 patients <21 years old with nonmetastatic synovial sarcoma were registered in 9 different countries (and 60 centers). Patients were treated with a multimodal therapy including ifosfamide-doxorubicin chemotherapy and radiotherapy, according to a risk stratification based on surgical stage, tumor size and site, and nodal involvement. RESULTS: With a median follow-up of 52.1 months (range 13.8-104.4 months), event-free survival (EFS) was 81.9% and 80.7%, and overall survival (OS) was 97.2% and 90.7%, at 3 and 5 years, respectively. The only significant prognostic variable at univariate analysis was the risk group: 3-year EFS was 91.7% for low-risk, 91.2% for intermediate-risk, and 74.4% for high-risk cases. In 24 low-risk patients (completely resected tumor ≤5 cm in size) treated with surgery alone, there were two local relapses and no metastatic recurrences. Among 67 high-risk patients (unresected, or axial tumor or nodal involvement), 66 underwent surgery after neoadjuvant chemotherapy. Response to chemotherapy was 55.2%, including 22.4% cases with complete or major partial remissions, and 32.8% with minor partial remissions. CONCLUSION: This study demonstrates that collaborative prospective studies on rare pediatric sarcomas are feasible even on a European scale, with excellent treatment compliance. The overall results of treatment were satisfactory, with higher survival rates than those previously published by pediatric groups. Nonetheless, larger, international projects are needed, based on a cooperative effort of pediatric and adult oncologists. CLINICAL TRIALS NUMBER: European Union Drug Regulating Authorities Clinical Trials No. 2005-001139-31.

Substitution of a hydroxamic acid anchor into the MK-2 dye for enhanced photovoltaic performance and water stability in a DSSC.

An efficient synthetic protocol to functionalize the cyanoacrylic acid anchoring group of commercially available MK-2 dye with a highly water-stable hydroxamate anchoring group is described. Extensive characterization of this hydroxamate-modified dye (MK-2HA) reveals that the modification does not affect its favorable optoelectronic properties. Dye-sensitized solar cells (DSSCs) prepared with the MK-2HA dye attain improved efficiency (6.9%), relative to analogously prepared devices with commercial MK-2 and N719 dyes. The hydroxamate anchoring group also contributes to significantly increased water stability, with a decrease in the rate constant for dye desorption of MK-2HA relative to MK-2 in the presence of water by as much as 37.5%. In addition, the hydroxamate-anchored dye undergoes essentially no loss in DSSC efficiency and the external quantum efficiency improves when up to 20% water is purposefully added to the electrolyte. In contrast, devices prepared with the commercial dye suffer a 50% decline in efficiency under identical conditions, with a concomitant decrease in external quantum efficiency. Collectively, our results indicate that covalent functionalization of organic dyes with hydroxamate anchoring groups is a simple and efficient approach to improving the water stability of the dye-semiconductor interface and overall device durability.

Are we ready to "think ahead"? Acceptability study using an innovative end of life planning tool.

This is a cross sectional study in 5 GP Training Practices, sample size 100 clinically stable patients, attending for routine care. Purpose of the study was explained and informed written consent was sought. Participants were provided with 'Think Ahead,' an innovative end of life planning tool, devised by The Forum on The End of Life, based on best international practice, presented in a questionnaire format, detailing main decision centres relevant in end of life planning. Participants completed telephone surveys at 1 and 3 weeks, ascertaining their experience with 'Think Ahead;' 92/100 completed both surveys. Results indicate high levels of acceptability and positive experience for most participants. A majority (63%) indicated 'no difficulty' in completing 'Think Ahead;' 74% indicated reported they did not find completing the folder to cause upset; 87% indicated they felt the folder should be more widely available, and 68% indicated they felt 'Think Ahead' would be of general interest. The study was effective in encouraging discussion on end of life issues with family (83%) with 49% indicating they had done so in detail, and 34% indicating having 'done so somewhat,' having read 'Think Ahead; 27% indicated aspects of it were upsetting. Results will be used to inform further development of the tool. General Practice consulting is a suitable context in which to systematically present 'Think Ahead.'

Safety, tolerability, and pharmacokinetics of ribavirin in hepatitis C virus-infected patients with various degrees of renal impairment.

Ribavirin (RBV) is an integral part of standard-of-care hepatitis C virus (HCV) treatments and many future regimens under investigation. The pharmacokinetics (PK), safety, and tolerability of RBV in chronically HCV-infected patients with renal impairment are not well defined and were the focus of an open-label PK study in HCV-infected patients receiving RBV plus pegylated interferon. Serial RBV plasma samples were collected over 12 h on day 1 of weeks 1 and 12 from patients with moderate renal impairment (creatinine clearance [CLCR], 30 to 50 ml/min; RBV, 600 mg daily), severe renal impairment (CLCR, <30 ml/min; RBV, 400 mg daily), end-stage renal disease (ESRD) (RBV, 200 mg daily), or normal renal function (CLCR, >80 ml/min; RBV, 800 to 1,200 mg daily). Of the 44 patients, 9 had moderately impaired renal function, 10 had severely impaired renal function, 13 had ESRD, and 12 had normal renal function. The RBV dose was reduced because of adverse events (AEs) in 71% and 53% of severe and moderate renal impairment groups, respectively. Despite this modification, patients with moderate and severe impairment had 12-hour (area under the concentration-time curve from 0 to 12 h [AUC0-12]) values 36% (38,452 ng · h/ml) and 25% (35,101 ng · h/ml) higher, respectively, than those with normal renal function (28,192 ng · h/ml). Patients with ESRD tolerated a 200-mg daily dose, and AUC0-12 was 20% lower (22,629 ng · h/ml) than in patients with normal renal function. PK modeling and simulation (M&S) indicated that doses of 200 mg or 400 mg alternating daily for patients with moderate renal impairment and 200 mg daily for patients with severe renal impairment were the most appropriate dose regimens in these patients.

Paediatric and adolescent alveolar soft part sarcoma: A joint series from European cooperative groups.

BACKGROUND: Alveolar soft part sarcomas (ASPS) are generally chemo- and radio-resistant mesenchymal tumours, with no standardized treatment guidelines. We describe the clinical behaviour of paediatric ASPS and compare these features to previously reported adult series. PATIENTS AND METHODS: The clinical data of 51 children and adolescents with ASPS, prospectively enrolled in or treated according to seven European Paediatric trials were analysed. RESULTS: Median age was 13 years [range: 2-21]. Primary sites included mostly limbs (63%). IRS post-surgical staging was: IRS-I (complete resection) 35%, II (microscopic residual disease) 20%, III (gross residual disease) 18% and IV (metastases) 27%. Only 3 of the 18 evaluable patients (17%) obtained a response to conventional chemotherapy. After a median follow-up of 126 months (range: 9-240), 14/18 patients with IRS-I tumour, 10/10 IRS-II, 7/9 IRS-III and 2/14 IRS-IV were alive in remission. Sunitinib treatment achieved two very good partial responses in four patients. Ten-year overall survival (OS) and event free survival (EFS) was 78.0 ± 7% and 62.8 ± 7% respectively. Stage IV, size >5 cm and T2 tumours had a poorer outcome, but only IRS staging was an independent prognostic factor. CONCLUSIONS: ASPS is a very rare tumour frequently arising in adolescents and in the extremities, and chemo resistant. Local surgical control is critical. ASPS is a poorly chemo sensitive tumour. For IRS-III/IV tumours, delayed radical local therapies including surgery are essential. Metastatic patients had a poor prognosis but targeted therapies showed promising results.

Influence of chronic hepatitis C infection on cytochrome P450 3A4 activity using midazolam as an in vivo probe substrate.

PURPOSE: Inflammation-related changes in pharmacokinetics have been described for a number of disease-states including cancer, infection, and autoimmune disorders. This study examined the impact of chronic hepatitis C infection (CHC) on the pharmacokinetics of the cytochrome P450 3A probe midazolam in patients without significant liver disease who were either treatment naïve or prior interferon null-responders. METHODS: Data were pooled from three studies which compared the pharmacokinetics of oral midazolam in healthy volunteers (n = 107) and in treatment-naive patients (n = 35) and interferon-null responders (n = 24) with CHC but without significant liver disease. Oral midazolam was administered as a single 2 mg oral dose, followed by frequent pharmacokinetic sampling and determination of the pharmacokinetics of midazolam and its α-hydroxy metabolite. CYP3A activity was determined by the metabolic ratio (MR) of the AUC metabolite/AUC parent and compared across groups as the mean effect ratio (test/reference). RESULTS: The midazolam MR was lower in treatment-naïve patients with CHC than in health volunteers with a mean effect ratio of 0.63 [90 % confidence interval (CI) 0.56-0.72]. The effect was more pronounced in null-responders, who demonstrated a mean MR effect ratio of 0.46 (90 % CI 0.39-0.53) compared to volunteers. The mean area under the concentration-time curve (AUCinf) for midazolam in healthy volunteers, naïve patients, and null-responders was 32.3 [coefficient of variation (CV%) 41], 36.5 (CV% 33.5), and 55.3 (CV% 36.9) ng.h/mL, respectively. CONCLUSIONS: The results of this study demonstrate a reduction in CYP3A4 activity between healthy volunteers and patients with CHC, with interferon null-responders demonstrating the most substantial difference. These results may have implications for the pharmacotherapy of patients infected with CHC.

Rare cancers in children - The EXPeRT Initiative: a report from the European Cooperative Study Group on Pediatric Rare Tumors.

The low incidence and the heterogeneity of very rare tumors (VRTs) demand for international cooperation. In 2008, EXPeRT (European Cooperative Study Group for Pediatric Rare Tumors) was founded by national groups from Italy, France, United Kingdom, Poland and Germany. The first aims of EXPeRT were to agree on a uniform definition of VRTs and to develop the currently most relevant scientific questions. Current initiatives include international data exchange, retrospective and prospective studies of specific entities, and the development of harmonized and internationally recognized guidelines. Moreover, EXPeRT established a network for expert consultation to assist in clinical decision in VRTs.

Rhabdomyosarcoma of the trachea: first reported case treated with proton beam therapy.

OBJECTIVE: We report a case of rhabdomyosarcoma of the trachea in a 14-month-old child, and we present the first reported use of proton beam therapy for this tumour. CASE REPORT: A 14-month-old girl presented acutely with a seven-day history of biphasic stridor. Emergency endoscopic debulking of a posterior tracheal mass was undertaken. Histological examination revealed an embryonal rhabdomyosarcoma with anaplasia. Multimodality therapy with surgery and chemotherapy was administered in the UK, and proton beam therapy in the USA. CONCLUSION: Only three cases of rhabdomyosarcoma of the trachea have previously been reported in the world literature. This is the first reported case of treatment of this tumour with proton beam therapy. Compared with conventional radiotherapy, proton beam therapy may confer improved long-term outcome in children, with benefits including reduced irradiation of the spinal cord.

The pharmacokinetics of peginterferon alfa-2a and ribavirin in African American, Hispanic and Caucasian patients with chronic hepatitis C.

BACKGROUND: Amongst Caucasian, Hispanic and African Americans with genotype 1 hepatitis C virus (HCV), there is a wide variation in response to treatment with peginterferon alfa-2a (PEG-IFN alfa-2a) and ribavirin. AIM: To evaluate the pharmacokinetics (PK) of PEG-IFN alfa-2a and ribavirin among these three groups. METHODS: Forty-seven patients with genotype 1 CHC (17 African Americans, 14 Hispanics and 16 Caucasians) received 8 weeks of PEG-IFN alfa-2a (180 µg/week) and ribavirin (1000 or 1200 mg/day). PEG-IFN alfa-2a serum concentrations and ribavirin plasma concentrations were measured following the first dose and at week 8. Pharmacokinetic parameters (C(max), T(max), AUC, CL/F) were estimated using noncompartmental methods. RESULTS: There was no difference in the pharmacokinetic parameters for PEG-IFN alfa-2a following single-dose or steady-state administration between African American or Hispanic patients compared with Caucasian patients. Ribavirin pharmacokinetic parameters were similar between Hispanic and Caucasian patients for single-dose and steady-state administration. The single-dose C(max) was 33% lower (P < 0.05) in African American compared with Caucasian patients. Other ribavirin single-dose and steady-state pharmacokinetic parameters were slightly decreased (approximately 20% lower) in African American patients, but were not considered clinically meaningful. CONCLUSIONS: No differences were observed in PEG-IFN alfa-2a pharmacokinetic parameters between African American or Hispanic patients compared with Caucasian patients. For ribavirin, no differences were observed in pharmacokinetic parameters between Hispanic and Caucasian patients. While a trend towards increased ribavirin clearance and decreased exposure was observed in African American patients vs. Caucasian patients, the differences were small and not considered clinically meaningful (Clinical Trial Number: NP17354).

Neural correlates of contextual cueing are modulated by explicit learning.

Contextual cueing refers to the facilitated ability to locate a particular visual element in a scene due to prior exposure to the same scene. This facilitation is thought to reflect implicit learning, as it typically occurs without the observer's knowledge that scenes repeat. Unlike most other implicit learning effects, contextual cueing can be impaired following damage to the medial temporal lobe. Here we investigated neural correlates of contextual cueing and explicit scene memory in two participant groups. Only one group was explicitly instructed about scene repetition. Participants viewed a sequence of complex scenes that depicted a landscape with five abstract geometric objects. Superimposed on each object was a letter T or L rotated left or right by 90°. Participants responded according to the target letter (T) orientation. Responses were highly accurate for all scenes. Response speeds were faster for repeated versus novel scenes. The magnitude of this contextual cueing did not differ between the two groups. Also, in both groups repeated scenes yielded reduced hemodynamic activation compared with novel scenes in several regions involved in visual perception and attention, and reductions in some of these areas were correlated with response-time facilitation. In the group given instructions about scene repetition, recognition memory for scenes was superior and was accompanied by medial temporal and more anterior activation. Thus, strategic factors can promote explicit memorization of visual scene information, which appears to engage additional neural processing beyond what is required for implicit learning of object configurations and target locations in a scene.

Results of a phase I/II study of ocrelizumab, a fully humanized anti-CD20 mAb, in patients with relapsed/refractory follicular lymphoma.

BACKGROUND: Ocrelizumab is a humanized anti-CD20 antibody with increased antibody-dependent cellular cytotoxicity compared with rituximab. This phase I/II study evaluated its safety and efficacy in patients with relapsed/refractory follicular lymphoma (FL) after prior rituximab therapy. DESIGN AND METHODS: Forty-seven patients were treated in three dose cohorts and received eight infusions every 3 weeks: cohort A, 200 mg/m(2) (n = 15); cohort B, 375 mg/m(2) (n = 16); cohort C, first dose 375 mg/m(2), seven subsequent doses of 750 mg/m(2) (n = 16). Patients were assessed for safety, efficacy, pharmacodynamics and pharmacokinetics. RESULTS: The median patient age was 58 years, the majority had Ann Arbor stage III/IV disease and had received a median of 2 (range 1-6) prior regimens. Ocrelizumab was well tolerated with grade 3/4 toxicity occurring in 9% of patients. The most common toxicity was infusion-related reactions (74% patients), all grade 1/2 except one grade 3 event. The objective response rate was 38% and was similar in patients with low-affinity and high-affinity variants of the Fcgamma receptor IIIa (FcgammaRIIIa). With follow-up of approximately 28 months, the median progression-free survival was 11.4 months. CONCLUSION: Ocrelizumab demonstrated activity in patients with relapsed/refractory FL following prior rituximab treatment, with safety similar to rituximab although adverse events appeared milder.

MELF pattern invasion in endometrial carcinoma: association with low grade, myoinvasive endometrioid tumours, focal mucinous differentiation and vascular invasion.

AIMS: To investigate the frequency of microcystic, elongated and fragmented (MELF) pattern invasion in endometrial carcinoma and its association with other pathological findings. METHODS: The histology slides from 170 consecutively accessioned endometrial malignancies were reviewed to identify cases showing MELF type invasion. Histological subtype, tumour grade, presence of squamous and mucinous differentiation, and frequency of lymphovascular space invasion (LVSI) were compared in MELF positive and negative cases. Additional stains for cytokeratin and stromal mucin were performed in the MELF positive tumours and immunohistochemistry to demonstrate vascular endothelium was performed in 12 selected cases. RESULTS: There were 133 endometrioid adenocarcinomas (EEC) and 37 non-endometrioid carcinomas. MELF type invasion was identified in 27 cases (15.9%) all of which were FIGO grade 1 or 2 myoinvasive adenocarcinomas of endometrioid type. The histochemical and immunohistochemical stains were useful in demonstrating the relatively subtle invasive foci in some tumours. MELF positive cases more frequently showed focal mucinous differentiation and LVSI. CONCLUSIONS: MELF type invasion appears restricted to low grade, myoinvasive carcinomas of endometrioid type and is more common in tumours exhibiting focal mucinous differentiation. These associations suggest that MELF changes represent a specific tumour-stromal interaction rather than a degenerative process. Tumours exhibiting MELF pattern invasion should be carefully examined for LVSI. Ancillary techniques, in particular cytokeratin immunohistochemistry, are useful in diagnostic assessment.