Community-based recruitment of patients with COPD into clinical research.

Identifying subjects for clinical trials is difficult and the evidence base for recruitment strategies is limited, particularly in the field of COPD. We compared the efficiency and patient characteristics of different community-based recruitment strategies during a non-commercial COPD trial in the UK. Recruiting from general practice COPD registers was less efficient and identified patients with significantly milder disease than recruiting through pulmonary rehabilitation and patient groups. We report our experience and propose that pulmonary rehabilitation and patient groups may represent an enriched pool of COPD patients to recruit into clinical trials

Effects of different antibiotic classes on airway bacteria in stable COPD using culture and molecular techniques: a randomised controlled trial

Long-term antibiotic therapy is used to prevent exacerbations of COPD but there is uncertainty over whether this reduces airway bacteria. The optimum antibiotic choice remains unknown. We conducted an exploratory trial in stable patients with COPD comparing three antibiotic regimens against placebo

Challenges and opportunities in resuming spirometry services in England post-pandemic with potential to adopt Artificial Intelligence decision support software: a qualitative study

Background: Spirometry services to diagnose and monitor lung disease in primary care are restarting post-pandemic in England, identified as a priority in the NHS Long Term Plan, however evidence regarding best practice is limited.Aims: To explore perspectives on spirometry provision in primary care, and the potential for Artificial Intelligence (AI) decision support software to aid quality and interpretation.Design and Setting: Semi-structured interviews with stakeholders in spirometry services in primary care.Methods: Semi-structured interviews were conducted with key stakeholders in spirometry services across England. Participants were recruited by snowball sampling. Interviews explored the pre-pandemic delivery of spirometry, restarting of services and perceptions of the role of AI. Transcripts were analysed thematically.Results: 28 participants (mean [SD], 21.6 [9.4, range 3-40] years’ clinical experience) were interviewed between April and June 2022. Participants included clinicians (n=25) and commissioners (n=3); eight held regional and/or national respiratory network advisory roles. Four themes were identified: 1) Historical challenges in spirometry provision; 2) Inequity in post-pandemic spirometry provision and challenges to restarting spirometry in primary care; 3) Future delivery closer to patients’ homes by appropriately trained staff; 4) The potential for AI to have supportive roles in spirometry.Conclusion: Stakeholders highlighted historic challenges and the damaging effects of the pandemic contributing to inequity in provision of spirometry, which must be addressed. Overall stakeholders were positive about the potential of AI to support clinicians in quality assessment and interpretation of spirometry. However, it was evident that validation of the software must be sufficiently robust for clinicians and healthcare commissioners to have trust in the process

The VASCERN-VASCA Working Group Diagnostic and Management Pathways for Venous Malformations.

UNLABELLED To elaborate expert consensus patient pathways to guide patients and physicians toward efficient diagnostics and management of patients with venous malformations. METHODS VASCERN-VASCA (https://vascern.eu/) is a European network of multidisciplinary centers for Vascular Anomalies. The Nominal Group Technique was used to establish the pathways. Two facilitators were identified: one to propose initial discussion points and draw the pathways, and another to chair the discussion. A dermatologist (AD) was chosen as first facilitator due to her specific clinical and research experience. The draft was subsequently discussed within VASCERN-VASCA monthly virtual meetings and annual face-to-face meetings. RESULTS The Pathway starts from the clinical suspicion of a venous type malformation (VM) and lists the clinical characteristics to look for to support this suspicion. Strategies for subsequent imaging and histopathology are suggested. These aim to inform on the diagnosis and to separate the patients into 4 subtypes: (1) sporadic single VMs or (2) multifocal, (3) familial, multifocal, and (4) combined and/or syndromic VMs. The management of each type is detailed in subsequent pages of the pathway, which are color coded to identify sections on (1) clinical evaluations, (2) investigations, (3) treatments, and (4) associated genes. Actions relevant to all types are marked in separate boxes, including when imaging is recommended. When definite diagnoses have been reached, the pathway also points toward disease-specific additional investigations and recommendations for follow up. Options for management are discussed for each subtype, including conservative and invasive treatments, as well as novel molecular therapies. CONCLUSION The collaborative efforts of VASCERN-VASCA, a network of the 9 Expert Centers, has led to a consensus Diagnostic and Management Pathways for VMs to assist clinicians and patients. It also emphasizes the role of multidisciplinary expert centers in the management of VM patients. This pathway will become available on the VASCERN website (http://vascern.eu/)

The VASCERN-VASCA working group diagnostic and management pathways for severe and/or rare infantile hemangiomas

The European Reference Network on Rare Multisystemic Vascular Diseases (VASCERN), is dedicated to gathering the best expertise in Europe and provide accessible cross-border healthcare to patients with rare vascular dis-eases. Infantile Hemangiomas (IH) are benign vascular tumors of infancy that rapidly growth in the first weeks of life, followed by stabilization and spontaneous regression. In rare cases the extent, the localization or the number of lesions may cause severe complications that need specific and careful management. Severe IH may be life-threatening due to airway obstruction, liver or cardiac failure or may harbor a risk of functional impairment, severe pain, and/or significant and permanent disfigurement. Rare IHs include syndromic variants associated with extracutaneous abnormalities (PHACE and LUMBAR syndromes), and large segmental hemangiomas. There are publications that focus on evidence-based medicine on propranolol treatment for IH and consensus state -ments on the management of rare infantile hemangiomas mostly focused on PHACES syndrome. The Vascular Anomalies Working Group (VASCA-WG) decided to develop a diagnostic and management pathway for severe and rare IHs with a Nominal Group Technique (NGT), a well-established, structured, multistep, facilitated group meeting technique used to generate consensus statements. The pathway was drawn following two face-to-facePeer reviewe

The VASCERN-VASCA working group diagnostic and management pathways for lymphatic malformations

Lymphatic malformations (LMs) are developmental defects of lymphatic vessels. LMs are histologically benign lesions, however, due to localization, size, and unexpected swelling, they may cause serious complications that threaten vital functions such as compression of the airways. A large swelling of the face or neck may also be disfiguring and thus constitute a psychological strain for patients and their families. LMs are also highly immunologically reactive, and are prone to recurrent infections and inflammation causing pain as well as chronic oozing wounds.The European Reference Network on Rare Multisystemic Vascular Diseases (VASCERN) is dedicated to gathering the best expertise in Europe. There are only few available guidelines on management and follow up of LMs, which commonly focus on very specific situations, such as head and neck LM (Zhou et al., 2011). It is still unclear, what constitutes an indication for treatment of LMs and how to follow up the patients. The Vascular Anomalies Working Group (VASCA-WG) of VASCERN decided to develop a diagnostic and management pathway for the management of LMs with a Nominal Group Technique (NGT), a well-established, structured, multistep, facilitated group meeting technique used to generate consensus statements. The pathway was drawn following 2 face-to-face meetings and multiple web meetings to facilitate discussion, and by mail to avoid the influence of most authoritative members.The VASCA-WG has produced this opinion statement reflecting strategies developed by experts and patient representatives on how to approach patients with lymphatic malformations in a practical manner; we present an algorithmic view of the results of our work.Peer reviewe

Characterisation and radioimmunotherapy of L19-SIP, an anti-angiogenic antibody against the extra domain B of fibronectin, in colorectal tumour models

Angiogenesis is a characteristic feature of tumours and other disorders. The human monoclonal antibody L19- SIP targets the extra domain B of fibronectin, a marker of angiogenesis expressed in a range of tumours. The aim of this study was to investigate whole body distribution, tumour localisation and the potential of radioimmunotherapy with the L19-small immunoprotein (SIP) in colorectal tumours. Two colorectal tumour models with highly different morphologies, the SW1222 and LS174T xenografts, were used in this study. Localisation and retention of the L19-SIP antibody at tumour vessels was demonstrated using immunohistochemistry and Cy3-labelled L19-SIP. Whole body biodistribution studies in both tumour models were carried out with 125I-labelled L19-SIP. Finally, 131I-labelled antibody was used to investigate the potential of radioimmunotherapy in SW1222 tumours. Using immunohistochemistry, we confirmed extra domain B expression in the tumour vasculature. Immunofluorescence demonstrated localisation and retention of injected Cy3-labelled L19-SIP at the abluminal side of tumour vessels. Biodistribution studies using a 125I-labelled antibody showed selective tumour uptake in both models. Higher recorded values for localisation were found in the SW1222 tumours than in the LS174T (7.9 vs 6.6 %ID g−1), with comparable blood clearance for both models. Based on these results, a radioimmunotherapy study was performed in the SW1222 xenograft using 131I-Labelled L19-SIP (55.5 MBq), which showed selective tumour uptake, tumour growth inhibition and improved survival. Radio- and fluorescence-labelled L19-SIP showed selective localisation and retention at vessels of two colorectal xenografts. Furthermore, 131I-L19-SIP shows potential as a novel treatment of colorectal tumours, and provides the foundation to investigate combined therapies in the same tumour models

Human monoclonal antibodies targeting carbonic anhydrase IX for the molecular imaging of hypoxic regions in solid tumours

BACKGROUND: Hypoxia, which is commonly observed in areas of primary tumours and of metastases, influences response to treatment. However, its characterisation has so far mainly been restricted to the ex vivo analysis of tumour sections using monoclonal antibodies specific to carbonic anhydrase IX (CA IX) or by pimonidazole staining, after the intravenous administration of this 2-nitroimidazole compound in experimental animal models.METHODS: In this study, we describe the generation of high-affinity human monoclonal antibodies (A3 and CC7) specific to human CA IX, using phage technology.RESULTS: These antibodies were able to stain CA IX ex vivo and to target the cognate antigen in vivo. In one of the two animal models of colorectal cancer studied (LS174T), CA IX imaging closely matched pimonidazole staining, with a preferential staining of tumour areas characterised by little vascularity and low perfusion. In contrast, in a second animal model (SW1222), distinct staining patterns were observed for pimonidazole and CA IX targeting. We observed a complementary pattern of tumour regions targeted in vivo by the clinical-stage vascular-targeting antibody L19 and the anti-CA IX antibody A3, indicating that a homogenous pattern of in vivo tumour targeting could be achieved by a combination of the two antibodies.CONCLUSION: The new human anti-CA IX antibodies are expected to be non-immunogenic in patients with cancer and may serve as broadly applicable reagents for the non-invasive imaging of hypoxia and for pharmacodelivery applications. British Journal of Cancer (2009) 101, 645-657. doi: 10.1038/sj.bjc.6605200 www.bjcancer.com Published online 21 July 2009 (C) 2009 Cancer Research U

Targeted microbubbles carrying lipid-oil-nanodroplets for ultrasound-triggered delivery of the hydrophobic drug, Combretastatin A4

The hydrophobicity of a drug can be a major challenge in its development and prevents the clinical translation of highly potent anti-cancer agents. We have used a lipid-based nanoemulsion termed Lipid-Oil-Nanodroplets (LONDs) for the encapsulation and in vivo delivery of the poorly bioavailable combretastatin A4 (CA4). Drug delivery with CA4 LONDs was assessed in a xenograft model of colorectal cancer. LC–MS/MS analysis revealed that CA4 LONDs, administered at a drug dose four times lower than drug control, achieved equivalent concentrations of CA4 intratumorally. We then attached CA4 LONDs to microbubbles (MBs) and targeted this construct to VEGFR2. A reduction in tumor perfusion was observed in CA4 LONDs-MBs treated tumors. A combination study with irinotecan demonstrated a greater reduction in tumor growth and perfusion (P = 0.01) compared to irinotecan alone. This study suggests that LONDs, either alone or attached to targeted MBs, have the potential to significantly enhance tumor-specific hydrophobic drug delivery