Immunology and Immunotherapy of high grade cervical lesions and cancer

Cervical cancer is caused by the human papillomavirus (HPV). The immune system plays an important role in the protection against HPV and failure of the immune system can lead to the development of cervical cancer. Immunotherapy aims at the restoration of an effective anti-tumour immunity. This thesis has led to new insights into the role of the immune system in HPV induced disease and forms a vital contribution to our understanding of tumor inducted immunesuppresion in patients with (pre-) cancerous lesions of the cervix. Furthermore it describes two clinical trails in which patients with pre-cancerous lesions of the cervix are vaccinated with an HPV16 E6/E7 synthetic overlapping long-peptide vaccine (HPV16-SLP). Multiple mechanisms restrain the host__s immune system to rise to the challenge of combating the tumour and favourable immune profiles need boosting in order to keep the balance in favour of tumour eradication. Future therapy should combine various synergistic approaches, and old and new therapies should be used side by side in order to enhance vaccination efficacy and counteract tumour suppression.ZonMWUBL - phd migration 201

Left Ventricular Unloading in Extracorporeal Membrane Oxygenation:A Clinical Perspective Derived from Basic Cardiovascular Physiology

Purpose of Review: To present an abridged overview of the literature and pathophysiological background of adjunct interventional left ventricular unloading strategies during veno-arterial extracorporeal membrane oxygenation (V-A ECMO). From a clinical perspective, the mechanistic complexity of such combined mechanical circulatory support often requires in-depth physiological reasoning at the bedside, which remains a cornerstone of daily practice for optimal patient-specific V-A ECMO care. Recent Findings: Recent conventional clinical trials have not convincingly shown the superiority of V-A ECMO in acute myocardial infarction complicated by cardiogenic shock as compared with medical therapy alone. Though, it has repeatedly been reported that the addition of interventional left ventricular unloading to V-A ECMO may improve clinical outcome. Novel approaches such as registry-based adaptive platform trials and computational physiological modeling are now introduced to inform clinicians by aiming to better account for patient-specific variation and complexity inherent to V-A ECMO and have raised a widespread interest. Summary: To provide modern high-quality V-A ECMO care, it remains essential to understand the patient's pathophysiology and the intricate interaction of an individual patient with extracorporeal circulatory support devices. Innovative clinical trial design and computational modeling approaches carry great potential towards advanced clinical decision support in ECMO and related critical care.</p

Vulvar cancer subclassification by HPV and p53 status results in three clinically distinct subtypes

Objective. There is great need for better risk stratification in vulvar squamous cell carcinoma (VSCC). Our aim was to define the prognostic significance of stratifying VSCC based on p16 and p53 immunohistochemistry (IHC) as surrogate markers for HPV and TP53 mutations. Methods. A large retrospective cohort of surgically treated women with primary VSCC was used. VSCC were classified into three subtypes: HPV-positive (HPVpos), HPV-negative/p53 mutant (HPVneg/p53mut), and HPVnegative/p53 wildtype (HPVneg/p53wt). Overall survival (OS), relative survival (RS), and recurrence-free period (RFP) were depicted using the Kaplan-Meier method and survival curves for relative survival; associations were studied using univariable and multivariable Cox proportional hazard models. Results. Of the 413 VSCCs, 75 (18%) were HPVpos, 63 (15%) HPVneg/p53wt, and 275 (66%) HPVneg/p53mut VSCC. Patients with HPVneg/p53mut VSCC had worse OS and RS (HR 3.43, 95%CI 1.80–6.53, and relative excess risk (RER) of 4.02; 95%CI 1.48–10.90, respectively, and worse RFP (HR 3.76, 95%CI 2.02–7.00). HPVpos VSCC patients showed most favorable outcomes. In univariate analysis, the molecular subtype of VSCC was a prognostic marker for OS, RS and RFP (p = 0.003, p = 0.009, p < 0.001, respectively) and remained prognostic for RFP even after adjusting for known risk factors (p = 0.0002). Conclusions. Stratification of VSCC by p16- and p53-IHC has potential to be used routinely in diagnostic pathology. It results in the identification of three clinically distinct subtypes and may be used to guide treatment and follow-up, and in stratifying patients in future clinical trials

Atrial septal defect in adults is associated with airway hyperresponsiveness

Objective: The association between secundum atrial septal defects (ASD) and asthma-like dyspnea with consequent long-term pulmonary inhalant use, is poorly understood in adult ASD patients. Airway hyperresponsiveness is suggested to be the underlying mechanism of cardiac asthma from mitral valve disease and ischemic cardiomyopathy. We hypothesized that airway hyperresponsiveness may also be found in adult ASD patients. Our aim was to study airway responsiveness in adult ASD patients before percutaneous closure and at short-and long-term postprocedural follow-up. Methods: This prospective study included 31 ASD patients (65% female, mean age 49 ± 15y) who underwent spirometry and bronchoprovocation testing pre-and six-month postprocedurally, with additional bronchoprovocation at 2-year follow-up. Airway hyperresponsiveness was defined as ≥20% fall of forced expiratory volume in 1-second (FEV1) following <8.0 mg/mL of inhaled methacholine. Results: Airway hyperresponsiveness was found in 19/30 patients (63%[95%CI 45%-81%]; post hoc statistical power = 89%). Asthma-like symptoms wheezing, chest tightness, and cough were more frequently reported in airway hyperresponsive patients. Airway responsiveness was not influenced by successful percutaneous ASD closure, corresponding to persistence of asthma-like symptoms postclosure. Regardless of airway responsiveness, postprocedural right-sided reverse remodeling significantly improved dyspnea and pulmonary function. Conclusions: This study is the first to report a high prevalence of airway hyperresponsiveness in a cohort of unrepaired adult ASD patients, and confirms the association between asthma-like symptoms and ASD in adults. Attention to symptoms and pulmonary function should be given during clinical follow-up of adult ASD patients, both before and long after repair

Airway inflammation and mannitol challenge test in COPD

ABSTRACT: BACKGROUND: Eosinophilic airway inflammation has successfully been used to tailor anti-inflammatory therapy in chronic obstructive pulmonary disease (COPD). Airway hyperresponsiveness (AHR) by indirect challenges is associated with airway inflammation. We hypothesized that AHR to inhaled mannitol captures eosinophilia in induced sputum in COPD. METHODS: Twenty-eight patients (age 58+/-7.8 yr, packyears 40+/-15.5, post-bronchodilator FEV1 77+/-14.0 %predicted, no inhaled steroids [greater than or equal to]4 wks) with mild-moderate COPD (GOLD I-II) completed two randomized visits with hypertonic saline-induced sputum and mannitol challenge (including sputum collection). AHR to mannitol was expressed as response-dose-ratio (RDR) and related to cell counts, ECP, MPO and IL-8 levels in sputum. RESULTS: There was a positive correlation between RDR to mannitol and eosinophil numbers (r=0.47, p=0.03) and level of IL-8 (r=0.46, p=0.04) in hypertonic saline-induced sputum. Furthermore, significant correlations were found between RDR and eosinophil numbers (r=0.71, p=0.001), level of ECP (r=0.72, p=0.001), IL-8 (r=0.57, p=0.015) and MPO (r=0.64, p=0.007) in sputum collected after mannitol challenge. ROC-curves showed 60% sensitivity and 100% specificity of RDR for >2.5% eosinophils in mannitol-induced sputum. CONCLUSIONS: In mild-moderate COPD mannitol hyperresponsiveness is associated with biomarkers of airway inflammation. The high specificity of mannitol challenge suggests that the test is particularly suitable to exclude eosinophilic airways inflammation, which may facilitate individualized treatment in COPD. Trial registration. Trialregister.nl number, NTR1283 (trailregister.nl

Tumor-infiltrating CD14-positive myeloid cells and CD8-positive T-cells prolong survival in patients with cervical carcinoma

Experimental cancer immunology and therap