Clinical Theranostics in Recurrent Gliomas: A Review.

Gliomas represent the most commonly occurring tumors in the central nervous system and account for approximately 80% of all malignant primary brain tumors. With a high malignancy and recurrence risk, the prognosis of high-grade gliomas is poor, with a mean survival time of 12-18 months. While contrast-enhanced MRI serves as the standard diagnostic imaging modality for gliomas, it faces limitations in the evaluation of recurrent gliomas, failing to distinguish between treatment-related changes and tumor progression, and offers no direct therapeutic options. Recent advances in imaging modalities have attempted to address some of these limitations, including positron emission tomography (PET), which has demonstrated success in delineating tumor margins and guiding the treatment of recurrent gliomas. Additionally, with the advent of theranostics in nuclear medicine, PET tracers, when combined with therapeutic agents, have also evolved beyond a purely diagnostic modality, serving both diagnostic and therapeutic roles. This review will discuss the growing involvement of theranostics in diagnosing and treating recurrent gliomas and address the associated impact on quality of life and functional recovery.

Mixed methods study to develop the content validity and the conceptual framework of the electronic patient-reported outcome measure for vascular conditions.

OBJECTIVE: The aim of this paper is to describe the stages undertaken to generate the items and conceptual framework of a new electronic personal assessment questionnaire for vascular conditions. DESIGN: A mixed methods study: First a survey of vascular clinicians was completed to identify the most common conditions treated in vascular clinics and wards. Quantitative systematic reviews were done to identify validated patient-reported outcome measures (PROMs) for direct inclsuion in the new instrument. However, due to scarcity of validated PROMs, the items of the new instrument were mainly based on a large qualitative study of patients and systematic reviews of the qualitative evidence . This was followed by a quantitative clinicians' consensus study and, finally, a qualitative face validity study with patients. PARTICIPANTS: Vascular patients participated in the primary qualitative study and the face validity study. In the qualitative study, 55 patients were interviewed, and for the face validity, 19 patients gave feedback. Twelve clinicians completed the survey and 13 completed two cycles of the clinicians' consensus study. RESULTS: The items and scales in the electronic personal assessment questionnaire for vascular conditions (ePAQ-VAS) were generated based on the results of five systematic reviews evaluating existing PROMs for possible inclusion in ePAQ-VAS, five systematic reviews of qualitative evidence, a primary qualitative study involving 55 patients and clinicians' input. One hundred and sixty-eight items were initially generated, of which 59 were eliminated by the expert panel due to repetition. The instrument was divided into one generic and three disease-specific sections (abdominal aortic aneurysm, carotid artery disease and lower limb vascular conditions). In each section, items were grouped together into putative scales. Fifty-five items were grouped across eight scales; the remaining items were kept as individual items, because of relevance to service users. CONCLUSIONS: This multidimensional electronic questionnaire covers the most common vascular conditions. This is particularly important for patients presenting with mixed symptoms or multiple conditions. This tool captures symptomatology, health related quality of life (HRQoL) and other clinically relevant data, such as experience with services and comorbidities.

Outcomes of aortic aneurysm surgery in England: a nationwide cohort study using hospital admissions data from 2002 to 2015.

BACKGROUND: The United Kingdom aortic aneurysms (AA) services have undergone reconfiguration to improve outcomes. The National Health Service collects data on all hospital admissions in England. The complex administrative datasets generated have the potential to be used to monitor activity and outcomes, however, there are challenges in using these data as they are primarily collected for administrative purposes. The aim of this study was to develop standardised algorithms with the support of a clinical consensus group to identify all AA activity, classify the AA management into clinically meaningful case mix groups and define outcome measures that could be used to compare outcomes among AA service providers. METHODS: In-patient data about aortic aneurysm (AA) admissions from the 2002/03 to 2014/15 were acquired. A stepwise approach, with input from a clinical consensus group, was used to identify relevant cases. The data is primarily coded into episodes, these were amalgamated to identify admissions; admissions were linked to understand patient pathways and index admissions. Cases were then divided into case-mix groups based upon examination of individually sampled and aggregate data. Consistent measures of outcome were developed, including length of stay, complications within the index admission, post-operative mortality and re-admission. RESULTS: Several issues were identified in the dataset including potential conflict in identifying emergency and elective cases and potential confusion if an inappropriate admission definition is used. Ninety six thousand seven hundred thirty-five patients were identified using the algorithms developed in this study to extract AA cases from Hospital episode statistics. From 2002 to 2015, 83,968 patients (87% of all cases identified) underwent repair for AA and 12,767 patients (13% of all cases identified) died in hospital without any AA repair. Six thousand three hundred twenty-nine patients (7.5%) had repair for complex AA and 77,639 (92.5%) had repair for infra-renal AA. CONCLUSION: The proposed methods define homogeneous clinical groups and outcomes by combining administrative codes in the data. These methodologically robust methods can help examine outcomes associated with previous and current service provisions and aid future reconfiguration of aortic aneurysm surgery services.

Long-Term Evaluation of Percutaneous Groin Access for EVAR.

BACKGROUND: Percutaneous endovascular aneurysm repair (PEVAR) has been shown to have high success rates, shorter operating times and length of stay compared to open access. However, there exists a lack of long-term follow-up data on these patients, and questions remain regarding longer-term outcomes. This study aims to assess the long-term complications and evolution of accessed vessels post-PEVAR. METHODS: Sixty-one cases of bilateral PEVAR (122 groins) with > 36 months follow-up were analysed. Vessel diameter, calcification, dissection, lymphocele, pseudoaneurysm and thrombus formation were reviewed at 30th day and at the most recent follow-up CT. Notes were reviewed for groin infections, haematomas and nerve injury. Complications were considered 'major' if they required intervention or treatment. RESULTS: Mean follow-up time from procedure to most recent scan was 49.9 months. There were no major short- or long-term complications. The early complication rate was 9.8%, with six pseudoaneurysms, four dissections, one thrombus, one nerve injury and no lymphoceles, haematomas or groin infections. The long-term complication rate was 0.8%, with only one pseudoaneurysm. The remainder of early complications resolved naturally without intervention. Accessed vessel showed significantly (P ≤ 0.05) increased diameter and calcification between 30th day and last follow-up scan. CONCLUSION: This study provides the largest clinical cohort and the longest mean follow-up time reported in the literature and demonstrates the long-term safety of PEVAR. PEVAR has a very low long-term complication rate, without any major complications in our cohort. The accessed common femoral arteries do not show stenosis or thrombosis. Minor short-term complications appear to gradually resolve without intervention. Larger multi-centre studies are recommended.

Cost-effectiveness of superficial femoral artery endovascular interventions in the UK and Germany: a modelling study.

OBJECTIVES: To assess the lifetime costs and cost-effectiveness of 5 endovascular interventions to treat superficial femoral arterial disease. DESIGN: A model-based health economic evaluation. An existing decision analytical model was used, with updated effectiveness data taken from the literature, and updated costs based on purchasing prices. SETTING: UK and German healthcare perspectives were considered. PARTICIPANTS: Patients with intermittent claudication of the femoropopliteal arteries eligible for endovascular treatment. METHODS: UK and German healthcare perspectives were considered, as were different strategies for re-intervention. INTERVENTIONS: Percutaneous transluminal angioplasty (PTA) with bail-out bare metal stenting (assumed to represent the existing standard of care, and 4 alternatives: primary bare metal stents, drug-eluting stents, drug-eluting balloons (DEBs) and biomimetic stents). PRIMARY OUTCOME MEASURES: The incremental cost-effectiveness ratio between 2 treatments, defined as the incremental costs divided by the incremental quality-adjusted life years (QALYs). RESULTS: Use of a biomimetic stent, BioMimics 3D, was always estimated to dominate the other interventions, having lower lifetime costs and greater effectiveness, as measured by QALYs. Of the remaining interventions, DEBs were always the most effective, and PTA the least effective. There was uncertainty in the cost-effectiveness results, with key drivers being the costs and effectiveness of the biomimetic stent along with the costs of DEBs. CONCLUSIONS: All 4 of the alternatives to PTA were more effective, with the biomimetic stent being the most cost-effective. As there was uncertainty in the results, and all of the interventions have different mechanisms of action, all 4 may be considered to be alternatives to PTA.

A detailed evaluation of the anatomical variations of the profunda artery perforator flap using computed tomographic angiograms.

BACKGROUND: The profunda artery perforator flap is a new option for breast reconstruction in appropriate patients. While the basic anatomy is known, detailed profunda perforator anatomy has never fully been described and we present new data that will aid dissection. METHODS: Fifty consecutive lower extremity computed tomography angiogram scans (100 legs) were retrospectively analyzed to acquire profunda artery perforator measurements. Patient medical records were then examined to ascertain patient information. Data were then analyzed using simple descriptive statistics and bivariate linear regressions with repeated measures. RESULTS: Bilateral thighs from 50 consecutive angiograms were included for a total of 100 thighs. Females comprised 30 (60 percent) of the patients and the cohort average age was 59.1 years old. All thighs had at least two perforators, with 85 percent having three or more. On average, perforators were located 6.2 cm below the gluteal crease, and were evenly distributed between the medial and lateral halves of the thigh. The average perforator diameter at origin off profunda was 2.7 mm. There was significantly greater diameter in vessels in the lateral thigh (p<0.001), in patients with higher Body Mass Index (BMI) (p<0.05), and in patients with decreased age (p<0.05). Males were more likely to have perforators that shared a common trunk off the profunda artery (p<0.05). CONCLUSIONS: At least two profunda perforators exist in each thigh with an average diameter suitable for microvascular transfer, although larger perforators are observed laterally and in younger patients with higher BMI.

Endovascular repair of abdominal aortic aneurysm.

BACKGROUND: An abnormal dilatation of the abdominal aorta is referred to as an abdominal aortic aneurysm (AAA). Due to the risk of rupture, surgical repair is offered electively to individuals with aneurysms greater than 5.5 cm in size. Traditionally, conventional open surgical repair (OSR) was considered the first choice approach. However, over the past two decades endovascular aneurysm repair (EVAR) has gained popularity as a treatment option. This article intends to review the role of EVAR in the management of elective AAA. OBJECTIVES: To assess the effectiveness of EVAR versus conventional OSR in individuals with AAA considered fit for surgery, and EVAR versus best medical care in those considered unfit for surgery. This was determined by the effect on short, intermediate and long-term mortality, endograft related complications, re-intervention rates and major complications. SEARCH METHODS: The Cochrane Peripheral Vascular Diseases Group Trials Search Co-ordinator (TSC) searched the Specialised Register (January 2013) and the Cochrane Central Register of Controlled Trials (CENTRAL) (2012, Issue 12). The TSC also searched trial databases for details of ongoing or unpublished studies. SELECTION CRITERIA: Prospective randomised controlled trials (RCTs) comparing EVAR with OSR in individuals with AAA considered fit for surgery. and comparing EVAR with best medical care in individuals considered unfit for surgery. We excluded studies with inadequate data or using an inadequate randomisation technique. DATA COLLECTION AND ANALYSIS: Three reviewers independently evaluated trials for appropriateness for inclusion and extracted data using pro forma designed by the Cochrane PVD Group. We assessed the quality of trials using The Cochrane Collaboration's 'Risk of bias' tool. We entered collected data in to Review Manager (version 5.2.3) for analysis. Where direct comparisons could be made, we determined odds ratios (OR). We tested studies for heterogeneity and, when present, we used a random-effects model; otherwise we used a fixed-effect model. We tabulated data that could not be collated. MAIN RESULTS: Four high-quality trials comparing EVAR with OSR (n = 2790) and one high-quality trial comparing EVAR with no intervention (n = 404) fulfilled the inclusion criteria. In individuals considered fit for surgery, a pooled analysis, including 1362 individuals randomised to EVAR and 1361 randomised to OSR, found short-term mortality (including 30-day or inhospital mortality, excluding deaths prior to intervention) with EVAR to be significantly lower than with OSR (1.4% versus 4.2%, OR 0.33, 95% confidence interval (CI) 0.20 to 0.55; P < 0.0001). Using intention-to-treat analysis (ITT) there was no significant difference in mortality at intermediate follow-up (up to four years from randomisation), with 221 (15.8%) and 237 (17%) deaths in the EVAR (n = 1393) and OSR (n = 1390) groups, respectively (OR 0.92, 95% CI 0.75 to 1.12; P = 0.40). There was also no significant difference in long-term mortality (beyond four years), with 464 (37.3%) deaths in the EVAR and 470 (37.8%) deaths in the OSR group (OR 0.98, 95% CI 0.83 to 1.15; P = 0.78). Similarly, there was no significant difference in aneurysm-related mortality between groups, either at the intermediate- or long-term follow up.Studies showed that both EVAR and OSR were associated with similar incidences of cardiac deaths (OR 1.14, 95% CI 0.86 to 1.52; P = 0.36) and fatal stroke rate (OR 0.81, 95% CI 0.42 to 1.55; P = 0.52). The long-term reintervention rate was significantly higher in the EVAR group than in the OSR group (OR 1.98, 95% CI 1.12 to 3.51; P = 0.02; I(2) = 85%). Results of the reintervention analysis should be interpreted with caution due to significant heterogeneity. Operative complications, health-related quality of life and sexual dysfunction were generally comparable between the EVAR and OSR groups. However, there was a slightly higher incidence of pulmonary complications in the OSR group compared with the EVAR group (OR 0.36, 95% CI 0.17 to 0.75; P = 0.006).In individuals considered unfit for conventional OSR, the one included trial found no difference between the EVAR and no-intervention groups with regard to all-cause mortality at final follow up, with 21.0 deaths per 100 person-years in the EVAR group and 22.1 deaths per 100 person years in the no-intervention group (adjusted hazard ratio (HR) with EVAR 0.99, 95% CI 0.78 to 1.27; P = 0.97). Aneurysm-related deaths were, however, significantly higher in the no-intervention group than in the EVAR group (adjusted HR 0.53, 95% CI 0.32 to 0.89; P = 0.02). There was no difference in myocardial events (HR 1.07, 95% CI 0.60 to 1.91) between the groups in this study. AUTHORS' CONCLUSIONS: In individuals considered fit for conventional surgery, EVAR was associated with lower short-term mortality than OSR. However, this benefit from EVAR did not persist at the intermediate- and long-term follow ups. Individuals undergoing EVAR had a higher reintervention rate than those undergoing OSR. Most of the reinterventions undertaken following EVAR, however, were catheter-based interventions associated with low mortality. Operative complications, health-related quality of life and sexual dysfunction were generally comparable between EVAR and OSR. However, there was a slightly higher incidence of pulmonary complications in the OSR group than in the EVAR group.In individuals considered unfit for open surgery, the results of a single trial found no overall short- or long-term benefits of EVAR over no intervention with regard to all-cause mortality, but individuals may differ and individual preferences should always be taken into account.

Direct interaction of GABAB receptors with M2 muscarinic receptors enhances muscarinic signaling.

Downregulation of G-protein-coupled receptors (GPCRs) provides an important mechanism for reducing neurotransmitter signaling during sustained stimulation. Chronic stimulation of M(2) muscarinic receptors (M(2)Rs) causes internalization of M(2)R and G-protein-activated inwardly rectifying potassium (GIRK) channels in neuronal PC12 cells, resulting in loss of function. Here, we show that coexpression of GABA(B) R2 receptors (GBR2s) rescues both surface expression and function of M(2)R, including M(2)R-induced activation of GIRKs and inhibition of cAMP production. GBR2 showed significant association with M(2)R at the plasma membrane but not other GPCRs (M(1)R, mu-opioid receptor), as detected by fluorescence resonance energy transfer measured with total internal reflection fluorescence microscopy. Unique regions of the proximal C-terminal domains of GBR2 and M(2)R mediate specific binding between M(2)R and GBR2. In the brain, GBR2, but not GBR1, biochemically coprecipitates with M(2)R and overlaps with M(2)R expression in cortical neurons. This novel heteromeric association between M(2)R and GBR2 provides a possible mechanism for altering muscarinic signaling in the brain and represents a previously unrecognized role for GBR2.

Outpatient vascular intervention: a two-year experience.

PURPOSE: To retrospectively analyze the outcome of a range of interventional vascular procedures performed on outpatients. METHODS: Suitability for outpatient procedures was assessed according to agreed protocols. An episode was defined as any procedure/s through a single access site at one attendance. Retrospective case-note review was performed. RESULTS: There were 693 outpatient episodes between April 1998 and May 2000 (290 interventional, and 403 diagnostic procedures), comprising 25% (693/2,769) of the total workload. Follow-up is available in 214; 38 of these were transfers from outlying hospitals and were excluded from analysis. One hundred and seventy-six were true outpatients. There were 98 iliac and 46 femoropopliteal interventions, 2 aortic stents, 1 renal and 5 upper-limb angioplasties (PTAs), 5 embolizations, 8 Hickman lines, 1 line stripping, 3 atherectomies, 1 dialysis-graft PTA and 6 bypass-graft PTAs. Sixty-eight closure devices were used. Twelve patients were converted to inpatients (6.8%, 12/176). The readmission rate was 3.4% (6/176). The reattendance rate was 1.1% (2/176), both subsequently attending for outpatient duplex ultrasound examination to exclude pseudoaneurysm. The major complication rate was 3.4% and the delayed major complication rate was 1.7%. CONCLUSION: Outpatient vascular intervention is safe with appropriate protocols and with careful patient selection. Local vascular services benefit from the release of inpatient beds.