Prevalence of possible immune resistance mechanisms of acute leukemias within the context of vaccination strategies using the Wilms tumor gene-1 (WT1)

Die Studie auf die diese Arbeit aufbaut untersuchte die Immunogenität einer Wilms-Tumorgenprodukt-1-(WT1)-Peptid-Vakzinierung bei Patienten mit einer WT1-exprimierenden akuten myeloischen Leukämie (AML) ohne weitere Behandlungsoption. Trotz dem initalen immunologischen, molekularen und vorläufigen Nachweis einer möglichen klinischen Effektivität bei AML-Patienten, konnte nur in wenigen Fällen eine längerfristige Wirksamkeit dokumentiert werden. Es ist bekannt, dass eine Krebs-Immuntherapie durch Immunevasions-Mechanismen des Tumors beeinträchtigt werden kann. Da Analysen zu Mutationen oder Verlust des WT1-Epitops oder Epitop-flankierender Sequenzen keine Auffälligkeiten zeigten, konnte eine reduzierte Präsentation oder Erkennung des Epitops ausgeschlossen werden. Aus diesem Grunde sollte diese Arbeit weitere mögliche Immunevasions-Mechanismen identifizieren. Als Grundlage wurden Tumor-assoziierte Effekte, immunmodulatorische Faktoren und funktionelle Einschränkungen der Immunzellen in den Mittelpunkt der Untersuchungen gestellt. Die ermittelten Daten zeigen, dass in unserem spezifischen Therapieansatz, der wiederholten Vakzinierung von AML-Patienten mit einem HLA-A201-restringierten WT1126–134 -Epitop in Kombination mit GM-CSF und KLH, eine eingeschränkte T-Zell-Funktionalität einen wesentlichen Grund für die beobachtete verminderte Therapieeffizienz darstellt. Immunresistenzmechanismen leukämischer Blasten spielen hierbei keine übergeordnete Rolle, individuelle Effekte können aber nicht ausgeschlossen werden. Ebenso scheint es, dass auch die Präsenz von immunregulatorischen Zellen wie Tregs oder MDSCs nicht durch die Vakzinierung manipuliert wird und dass diese keinen generellen Einfluss auf die Therapieeffizienz ausüben.The foregoing study investigated the immunogenicity of Wilms’ tumor gene product 1 (WT1)-peptide vaccination in WT1-expressing acute myeloid leukemia (AML) patients without curative treatment option. Despite the first immunologic, molecular, and preliminary evidence of potential clinical efficacy in AML patients, only in a few cases long-lasting responses could be documented. It is known that enduring efficacy of cancer vaccines may be limited due to immune escape mechanisms. On this account, we chose to work on three front lines: Investigations of immune modulatory counter-attack-mechanisms of the tumor, functional deficiencies of the T cell compartment and the presence of immune regulatory cells. The generated data demonstrates that in our specific setting, in which AML patients received consecutive vaccinations with HLA-A201-restricted WT1126–134 epitope together with GM-CSF and KLH, impaired vaccine efficacy is mainly attributed to restricted T cell functionality. Immune resistance mechanism exerted by leukemic blasts do not generally influence clinical outcome in our setting, neither do inert immunoregulative mechanisms like Treg or MDSC, respectively

The application of the rules of punctuation in typical business correspondence

Thesis (Ed.D.)--Boston UniversityStatement of the Problem The major purposes of this study were to determine which of the many rules of punctuation are commonly applied in modern business correspondence and to determine the degree of accuracy with whieh student·stenographers punctuate correspondence presented in written form for correction and in oral form for transcription [TRUNCATED

Notes on East Yorkshire Boulders

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Patient and Healthcare Professional Priorities for a Mobile Phone Application for Patients With Peripheral Arterial Disease

Introduction Supervised exercise therapy (SET) is the first-line treatment for the peripheral arterial disease (PAD), however, access and compliance are low. An alternative method of delivering this therapy is through mobile health applications, which can be more accessible and convenient for patients. The aim of this study is to evaluate patient, public and healthcare professional (HCP) priorities with regard to a dedicated mobile phone application to deliver remote SET. Methods Bespoke questionnaires were designed for patients and HCPs to assess app functionality and prioritisations for development. These were distributed through social media and the Norfolk and Norwich University Hospital. Results Functionality questionnaires were completed by 62 patients and 44 HCPs. Eighty-four per cent of patients wanted their therapy to be monitored by their vascular team with the majority (78%) interested in measuring walking distances. Most patients (76%) were interested in watching exercise videos. These views were shared by HCPs. A communication platform was prioritised for messaging and pictures by the patient (74% and 68% respectively), but not so by HCPs (40%). Documenting other forms of physical activity and the use of wearable technology was less valuable to patients but favoured by HCPs (50%). The ability to interact with other users was not prioritised by either group. Conclusion Delivery of a mobile phone application to deliver health programmes for SET in patients with PAD is an acceptable method for patients and HCPs. This data will enable the next stages of mobile phone application development to be appropriately prioritised, focusing on building exercise videos, a communication platform and further walking tests

Pro/con clinical debate: Tracheostomy is ideal for withdrawal of mechanical ventilation in severe neurological impairment

Most clinical trials on the topic of extubation have involved patients outside the neurological intensive care unit. As a result, in this area clinicians are left with little evidence on which to base their decision making. Although tracheostomies are increasingly common procedures, they are not without complications and costs, and hence a decision to perform them should not be taken lightly. In this issue of Critical Care two groups debate the merits of tracheostomy before extubation in a patient with neurological impairment. What becomes very clear is the need for more high quality data for this common clinical problem

Delayed Presentation of Hemothorax and Mediastinal Hematoma Requiring Surgical Intervention After Linear Endobronchial Ultrasound

A 55-year-old male with coronary artery disease status post drug-eluting stents in 2009, maintained on dual antiplatelet therapy (DAPT) with clopidogrel 75 mg daily and aspirin (ASA) 325 mg daily, and an 80 pack-year history of tobacco dependence was referred for evaluation of a right upper lobe lung nodule. No additional risk factors for bleeding were identified. Computed tomography of the chest showed a 29.0 mm spiculated right upper lobe nodule with right hilar and paratracheal lymphadenopathy. Poor functional status excluded him from possible curative intent surgery by previous thoracic surgery consultation

The risk of harm whilst waiting for varicose veins procedure.

INTRODUCTION: Varicose veins (VV) negatively impact quality of life (QoL) and have risks of major complications including bleeding, ulceration and phlebitis. During the COVID-19 pandemic, the VSGBI (Vascular Society of Great Britain and Ireland) and GIRFT (Get It Right First Time) classified VVs as lowest priority for intervention. OBJECTIVE: This study aims to determine harm caused and the impact on the QoL on patients waiting for their VVs procedures for more than 1 year. METHODS: This was a prospective study conducted at the Norfolk and Norwich University Hospital (NNUH). Patients with VVs awaiting intervention for >1 year were included in the study. Patients with CEAP C6 disease were considered to be too high risk to be invited for treatment during the Covid-19 pandemic. Patients were sent QoL questionnaires and underwent a telephone consultation to assess harm. Both generic (EQ-VAS and EQ-5D) and disease-specific (AVVQ and CIVIQ-14) instruments were utilised. There were no control groups available for comparison. RESULTS: 275 patients were identified (37.1% male) with median time on waiting list of 60 weeks (IQR 56-65). 19 patients (6.9%) came to major harm, including phlebitis (3.6%), bleeding (1.8%) and ulceration (1.8%). Fifty-two patients (18.9%) had minor harm, including worsening pain (12.7%) and swelling (6.2%). 6.9% reported psychological harm. Rising CEAP stage was also associated with worsening level of harm in patients with C5-6 disease (p < 0.0001). Only 8.7% stated they would decline surgery during the pandemic. 104 QoL questionnaires were returned. Median EQ-VAS and EQ-5D was 75 (IQR: 60-85) and 0.685 (0.566-0.761), respectively. Median AVVQ score was 23.2 (14.9-31.0) and CIVIQ-14 score was 33 (21-44).ConclusionsThis study highlights the impact of delaying VVs surgery during a pandemic. A significant rate of both major and minor as well as psychological harm was reported. In addition, VVs had a significant detriment to quality of life

Leg ulcer service provision in NHS hospitals

Leg ulcers are painful, distressing and common in the older population. They are costly to treat and put pressure on NHS providers. Compression therapy is the mainstay of treatment of venous leg ulceration. Aim: To explore the service provision for compression therapy for inpatients with leg ulcers in UK hospitals. Methods: An online survey was carried out to explore the service provision in hospital settings. It was distributed to Wounds UK National Conference delegates and to wound care specialist groups using social media. Results: The authors received 101 responses from health professionals in the UK. Of these, 67.3% reported there was no dedicated service for inpatients with leg ulceration and only 32% said compression therapy was provided in their hospitals. Conclusion: This survey confirmed there is a significant shortfall in care provision for patients with leg ulcers in secondary care and highlighted the wide variations in service delivery in hospitals. Further research is needed to understand the reasons for these variations

A systematic review and meta-analysis of enhanced recovery for open abdominal aortic aneurysm surgery

Introduction: Open abdominal aortic aneurysm (AAA) surgery is associated with significant morbidity, mortality and high length of stay (LOS). Enhanced recovery is now commonplace and has been shown to decrease these in other non-vascular surgery settings. This systematic review and meta-analysis aimed to assess the benefits of enhanced recovery (ERAS) in aortic surgery. Method: Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines were used to undertake a systematic review via Ovid MEDLINE and Embase on 10.07.2021. The search terms were “aortic aneurysm” and “fast track” or “enhanced recovery”. Data was obtained on major complications, 30-day mortality and LOS. Results: 107 papers were identified and 10 papers included for meta-analysis. Complication rates were significantly reduced with ERAS compared to non-ERAS protocols (ERAS n = 709, non-ERAS n = 930) (odds ratio.38,.22 to.65: P =.0005). LOS was also significantly reduced with an ERAS protocol (ERAS n = 708, non-ERAS n = 956) with a mean reduction of 3.18 days (−5.01 to −1.35 days) (P =.0007: I2 = 97%). There was no significant difference however in 30-day mortality (P =.92). Conclusion: This meta-analysis demonstrates significant benefits to an enhanced recovery programme in open AAA surgery. There is a need for a multi-centre randomized controlled trial to assess this further