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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Exercise Capacity, Lung Function, and Quality of Life After Interventional Bronchoscopy

Introduction:Malignant airway obstruction accounts for significant morbidity and mortality in patients with lung and metastatic cancer. We prospectively assessed the effects of bronchoscopic interventions for the treatment of malignant airway obstruction, with specific attention to exercise capacity and quality of life (QoL).Methods:This is a prospective cohort study. Patients with high-grade, symptomatic central malignant airway obstruction were assessed at baseline and then at days 30, 90, and 180 after bronchoscopic intervention with spirometry, 6-minute walk test (6MWT), and QoL and dyspnea questionnaires (European Organization for Research and Treatment of Cancer Quality of Life [C30] and Lung Cancer [LC-13] modules).Results:Thirty-seven patients were included in the final statistical analysis. Increases in 6MWT distance by 99.7 m (95% CI 33.2-166.2 m, p = 0.002), FEV1 by 448 ml (95% CI 203-692 ml, p < 0.001), and FVC by 416 ml (95% CI 130-702 ml, p = 0.003) were seen at day 30 compared with baseline. Clinically and statistically significant improvements were noted in composite dyspnea scores at day 30 by both QoL C30 (decrease of 39.9, 95% CI 21.4-58.4, p < 0.001) and LC-13 (decrease of 28.2, 95% CI 12.9-43.5, p < 0.001) questionnaires.Conclusions:Bronchoscopic intervention for malignant airway obstruction is associated with improvement in 6MWT, spirometry, and dyspnea at 30 days

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

Ligation alone versus immediate revascularization for femoral artery pseudoaneurysms secondary to intravascular drug use: A systematic review and meta-analysis

Background: Femoral artery pseudoaneurysms (FA-PSAs) remain a common vascular aneurysmal pathology associated with intravascular drug use (IVDU). To date no internationally agreed consensus regarding optimal surgical management of FA-PSAs exists. The aim of this systematic review and meta-analysis was to determine the optimal surgical treatment of FA-PSAs associated with IVDU. Methods: A systematic search was undertaken following PRISMA (Preferred Reporting Items for Systematic reviews and Meta-Analyses) guidelines identifying original studies reporting outcomes of ligation-debridement and/or excision-revascularization of FA-PSAs secondary to IVDU. Outcomes of interest were 30-day mortality, incidence of amputation at 12 months, chronic limb threatening ischemia (CLTI) at any follow-up appointment, reintervention, and bleeding. Results: A total of 39 cohort studies describing 1,217 FA-PSA operative outcomes met inclusion criteria, 993 (81.6%) treated by ligation-debridement and 224 (18.4%) by excision-revascularization. The incidence of 30-day mortality was 0.8% (n = 8) and 1.3% (n = 3) in the ligation-debridement and excision-revascularization groups, respectively, with only one study reporting mortality in both groups. This meta-analysis found no difference in amputation (8.89% vs. 8.03%, odds ratio (OR) 0.74 95% confidence interval (CI) 0.35–1.56, P = 0.42, 11 studies) or CLTI (21.5% vs. 12.4%, OR 1.24 95% CI 0.35–4.38, P = 0.74, 9 studies) after ligation and debridement compared with excision and revascularization. There was a higher incidence of reintervention (24.7% vs. 10.6%, OR 0.31 [95% CI 0.16, 0.62], P = 0.0009, 13 studies) and rebleeding (7.1% vs. 1.6%, OR 0.61 [95% CI 0.16, 2.38], P = 0.48, 5 studies) after excision and revascularization compared with ligation alone. Conclusions: For treatments of IVDU-related FA-PSAs, this study suggests no significant difference in association of mortality, incidence of amputation, or CLTI with ligation-debridement or excision-revascularization, but a significantly higher reintervention rate and greater rebleeding rate for revascularized patients

The Mysterious Risk of Arterial Thrombosis With COVID-19:A Case Series and Systematic Review of Acute Limb Ischaemia

Introduction: Coronavirus disease 2019 (COVID-19) generates a cytokine storm that predisposes patients to systemic complications including arterial thrombosis (AT) and acute limb ischaemia (ALI). This study reviews our understanding of the incidence and outcomes of patients with COVID-19 who develop AT. Methods: The case notes of all emergency patients with COVID-19 referred to the vascular services between March 2020 and March 2021 were reviewed. The study was undertaken to measure 30-day outcomes. Additionally, a literature search was undertaken according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines using the following search terms: acute limb ischaemia OR arterial thrombosis OR thrombectomy OR embolectomy AND COVID-19. Results: During March 2020 and March 2021, 60,000 people tested positive for COVID-19 in Norfolk. A total of 33 patients were referred to the vascular services, of which 15 had AT (estimated incidence of 0.03%). Of AT patients, 93% had ALL Fourteen locations of AT were identified. Of ATs, 36% were infrainguinal. The 30-day mortality was 60%. Three patients underwent surgery: two embolectomies (one requiring subsequent below-knee amputation (BKA) and the other died) and one primary BKA requiring subsequent above-knee amputation. The 30-day amputation-free survival (AFS) rate was 29%. The literature search identified 361 studies prior to a thorough full-text review. Nine case series were included with more than 10 participants each. The incidence of AT was reported as high as 15%. In-hospital mortality was 40%, with a significant proportion undergoing amputation or palliative care. Approximately a third of patients undergoing revascularisation subsequently re-occluded. AFS remained as low as 25%. Conclusion: The incidence of AT within the vascular surgery territory in COVID-19 patients is low; however, it is associated with poor 30-day AFS. A computed tomography angiography protocol including the entire major vessels may be indicated in COVID-19 patients