Recent Submissions

  • The onset, progress and factors influencing degenerative arthritis of the wrist following scaphoid fracture non-union

    Dias, Joseph; Kheiran, Amin; Adeleye, Emmanuel; Wildin, Clare; Ullah, Aamer; Bhowal, Bhaskar
    Background/aims: Scaphoid non-union causes osteoarthritis but factors associated are poorly understood. We investigated the rate of osteoarthritis after scaphoid fracture non-union, and if duration and fracture location influenced arthritis and its severity. Methods: This retrospective cross-sectional observational study of 278 consecutive cases with scaphoid fracture non-union retrieved data on demographics, non-union duration, fracture location, dorsal intercalated segment instability (DISI), severity and distribution of wrist arthritis. Patient Evaluation Measure (PEM) and Quality of Life assessed impact on patients. Regression models investigated prediction of osteoarthritis by different variables. Time-to-event analysis investigated osteoarthritis evolution. Missing (MAR) data for the PEM and QoL was imputed and analysed. Results: 278 patients, 246 males, aged 27.9 years (range 11 to 78 years), with a scaphoid fracture non-union confirmed on computed tomography (CT) scans (243) and plain radiographs (35) were reviewed. The interval between injury and imaging was 3.3 years (SD 5.9 years; range 0.1-45). The fracture was proximal to the ridge in 162, distal to the ridge in 83 and in the proximal 20% in 33. DISI (RLA ≥ 10°) occurred in 93.5% (260/278). Osteoarthritis was identified in 62.2% (173/278), and we classified a SNAC pattern in 93.6% (162/173). Of these, 100 (61.7%) had SNAC 1, 22 (13.6%) SNAC 2, 17 (10.5%) SNAC 3, and 23 (14.2%) SNAC 4. The mean duration in years for SNAC 1, 2, 3 and 4 were 2.5, 6.0, 8.2, and 11.3 years respectively. In fractures proximal to the ridge, 50% had arthritis in 2.2 years. Whereas in proximal pole, and distal to the ridge, 50% developed in 3.8 and 6.6 years, respectively. The PEM score was 42.8% (SD 18.9%) in those without arthritis and 48.8% (SD 21.5%) in those with arthritis. The mean QoL was 0.838 in patients without SNAC and 0.792 with SNAC. Conclusion: Scaphoid fracture non-union caused early carpal collapse, majority had osteoarthritis usually observed within a year following injury and occurred earliest in proximal waist fractures. Distribution of osteoarthritis (SNAC stage) may not always follow a distinctive pattern, as previously described.
  • Exercise rehabilitation in COPD and heart failure: comparison of two national audits

    Jones, Amy V.; Evans, Rachael; Steiner, Michael; Singh, Sally (2022-11)
    Background: Pulmonary (PR) and cardiac rehabilitation (CR) are recommended in the management of chronic obstructive pulmonary disease (COPD) and chronic heart failure (CHF); the impact of coexisting COPD and CHF on completion and outcomes of rehabilitation programmes is unknown. We examined enrolment, completion and clinical outcomes of CR and PR in adults with COPD, CHF and coexisting COPD and CHF. Methods: The National Audit of CR and National COPD Audit Programme: clinical audits of PR were analysed (211 PR and 237 CR programmes); adults with a diagnosis of CHF, COPD or coexisting COPD and CHF were identified (COPD+CHF or CHF+COPD according to database). Propensity matching was conducted (age, sex, body mass index and functional status) between COPD+CHF and COPD, and CHF+COPD and CHF. Group by time interaction was examined using mixed 2×2 analysis of variance. Results: Those with CHF+COPD had lower enrolment and completion of CR compared to those with CHF; there were no differences in PR enrolment or completion between the two groups. Adults with COPD made a significantly larger gain in the incremental shuttle walk test compared to adults with COPD+CHF following PR (59.3 m versus 37.4 m); the improvements following CR were similar (CHF 77.3 m versus CHF+COPD 58.3 m). Similar improvements were made in the 6-min walk test following CR (CHF 45.1 m versus CHF+COPD 38.8 m) and PR (COPD 48.2 m versus COPD+CHF 44.0 m). Comparable improvements in quality of life and mood state were made following CR and PR, regardless of diagnosis. Conclusion: We have demonstrated that multi-morbid adults benefit from exercise-based rehabilitation, yet efforts are needed to promote completion. These findings support group-based, tailored, multi-morbid exercise rehabilitation.
  • Identification of redundancy between human FcεRIβ and MS4A6A proteins points toward additional complex mechanisms for FcεRI trafficking and signaling

    Bradding, Peter
    Background: Allergic diseases are triggered by signaling through the high-affinity IgE receptor, FcεRI. In both mast cells (MCs) and basophils, FcεRI is a tetrameric receptor complex comprising a ligand-binding α subunit (FcεRIα), a tetraspan β subunit (FcεRIβ, MS4A2) responsible for trafficking and signal amplification, and a signal transducing dimer of single transmembrane γ subunits (FcεRIγ). However, FcεRI also exists as presumed trimeric complexes that lack FcεRIβ and are expressed on several cell types outside the MC and basophil lineages. Despite known differences between humans and mice in the presence of the trimeric FcεRI complex, questions remain as to how it traffics and whether it signals in the absence of FcεRIβ. We have previously reported that targeting FcεRIβ with exon-skipping oligonucleotides eliminates IgE-mediated degranulation in mouse MCs, but equivalent targeting in human MCs was not effective at reducing degranulation. Results: Here, we report that the FcεRIβ-like protein MS4A6A exists in human MCs and compensates for FcεRIβ in FcεRI trafficking and signaling. Human MS4A6A promotes surface expression of FcεRI complexes and facilitates degranulation. MS4A6A and FcεRIβ are encoded by highly related genes within the MS4A gene family that cluster within the human gene loci 11q12-q13, a region linked to allergy and asthma susceptibility. Conclusions: Our data suggest the presence of either FcεRIβ or MS4A6A is sufficient for degranulation, indicating that MS4A6A could be an elusive FcεRIβ-like protein in human MCs that performs compensatory functions in allergic disease.
  • Impact of Covid-19 on lung cancer and mesothelioma specialist nurses: A survey of experiences and perceptions

    Darlison, Liz (2022-12)
    Purpose: The covid-19 global pandemic has impacted on nurses who have rapidly adapted to new ways of working, and experienced negative impacts due to over-stretched services. Two surveys captured the experiences of lung cancer and mesothelioma specialist nurses in the United Kingdom (UK) in 2020, but the impact of later stages of the pandemic was unknown. This study aimed to explore the impact of covid-19 on lung Cancer and mesothelioma nurses since January 2021, the second wave of the pandemic. Methods: An online cross-sectional survey with both open and closed questions explored the impact of covid-19 on ways of working and workload, quality of care, and health and wellbeing. The survey was open to UK based lung cancer and mesothelioma advanced or specialist nurses. Results: 85 nurses responded to the survey. The majority were Clinical Nurse Specialists, based in England. Respondents reported changes in ways of working due to redeployment, staff shortages, and home working. Widespread adoption of virtual working practices led to concerns of negative impacts. Perceived excessive workload impacted on care with two-thirds of the sample (57, 67%) reporting they had been unable to provide the same quality of care to patients. Impacts on nurses' health and wellbeing were reported with two-thirds of the sample (56, 66%) reporting a deterioration in emotional wellbeing and mental health. Coping mechanisms employed included online team support to share experiences and increased uptake of exercise; however, impacts on lifestyle and access to coping mechanisms varied. Conclusion: Nurses have stepped up to the challenges of the pandemic with teamwork and innovation, but pressure arising from the pandemic and high workloads led to negative impacts on wellbeing. The authors have provided recommendations to improve patient care and support the wellbeing of nurses, which will be key to a resilient workforce living with covid-19. Whilst this study focussed on lung cancer and mesothelioma specialists, the findings have wider implications for other cancer specialties.
  • Cannabinoids in rheumatology: Friend, foe or a bystander?

    Jain, Nibha; Moorthy, Arumugam (2022-06)
    Objectives: Cannabinoids have gained popularity recently with special emphasis on their use for chronic pain. Although NICE guidelines advise against their usage for management of chronic pain, almost all rheumatologists encounter a few patients in their daily practice who either use them or are curious about them. We reviewed the mechanism of action of cannabinoids, current knowledge about their role in rheumatology and potential drug interactions with common drugs used in Rheumatology. We attempted to answer the question "If cannabinoids are friend, foe or just a mere bystander?" Methods: We adhered to a search strategy for writing narrative reviews as per available guidelines. We searched PubMed with the search terms "Cannabinoids", "Rheumatology" and "Chronic pain" for published articles and retrieved 613 articles. The abstracts and titles of these articles were screened to identify relevant studies focusing on mechanism of actions, adverse effects and drug interactions. We also availed the services of a musculoskeletal librarian. Results: Despite the NHS guidelines against the usage of cannabinoids and associated significant stigma, cannabinoids are increasingly used for the management of pain in rheumatology without prescription. Cannabinoids act through two major receptors CB1 and CB2, which are important modulators of the stress response with potential analgesic effects. Their role in various rheumatological diseases including Rheumatoid arthritis, Osteoarthritis and Fibromyalgia have been explored with some benefits. However, in addition to the adverse effects, cannabinoids also have some potential interactions with common drugs used in rheumatology, which many users are unaware of. Conclusion: While the current studies and patient reported outcomes suggest cannabinoids to be a "friend" of rheumatology, their adverse events and drug interactions prove to be a "Foe". We were unable to arrive at a definite answer for our question posed, however on the balance of probabilities we can conclude cannabinoids to be a "foe". Under these circumstances, a disease and drug focussed research is need of the hour to answer the unresolved question.
  • An update on the considerations for patients with rheumatic disease being treated with rituximab during the COVID-19 pandemic and the potential drug treatment strategies

    Moorthy, Arumugam
    Introduction: Over the last two decades, rituximab has become an increasingly popular drug in the treatment of a wide range of rheumatic diseases. However, with the advent of the COVID-19 pandemic, clinicians face challenges in weighing risk against benefit in its use. Areas covered: A review of existing data was performed to examine the relationship between rituximab use, morbidity and mortality from COVID-19, and vaccine efficacy in patients with rheumatic diseases, aiming to guide clinicians in continued use of the medication and consider the direction of future research. A literature review was performed through a search of the PubMed database, using the terms ((SARS-CoV-2) OR (COVID-19)) AND (rituximab) AND (rheumatic), which generated an initial 55 results, with relevant articles then selected for inclusion. Expert opinion: In order to safeguard patients with an ongoing need for rituximab therapy, vaccination remains the primary concern. A target of performing booster doses 6 months after last rituximab dose is a reasonable estimate, which may be made more precise by use of B cell counts, although primary immunization should not be delayed. In those patients who remain seronegative, the use of newer antivirals and broadly neutralizing antibody infusions may help provide further safeguards.
  • Giant cell arteritis with normal inflammatory markers

    Habib, Mohammad Bilal; Riaz, Afifa (2022-07)
  • Healing of ExcisionAl wounds on Lower legs by Secondary intention (HEALS) cohort study. Part 2: feasibility data from a multicentre prospective observational cohort study to inform a future randomized controlled trial

    Veitch, David (2022-10)
    Background: Compression therapy is considered beneficial for postsurgical lower leg wound healing by secondary intention; however, there is a lack of supportive evidence. To plan a randomized controlled trial (RCT), suitable data are needed. Aim: To determine the feasibility of recruitment and estimate recruitment rate; to understand the standard postoperative wound management pathway; to determine uptake of optional additional clinic visits for healing confirmation; and to explore patient acceptability of compression bandaging and plan a future RCT. Methods: Participant recruitment was performed from secondary care dermatology clinics, during a period of 22 months. Inclusion criteria were age ≥ 18 years, planned excision of keratinocyte cancer on the lower leg with healing by secondary intention and an ankle-brachial pressure index of ≥ 0.8. Exclusion criteria were planned primary closure/graft or flap; inability to receive, comply with or tolerate high compression; planned compression; or suspected melanoma. Patients were followed up weekly (maximum 6 months) in secondary care clinics and/or by telephone. Information was collected on healthcare resource use, unplanned compression, wound healing and an optional clinic visit to confirm healing. Results: This study recruited 58 patients from 9 secondary care dermatology clinics over 22 months. Mean recruitment/centre/month was 0.8 (range 0.1-2.3). Four centres had dedicated Research Nurse support. The analysis population (n = 53) had weekly follow-up assessments. Standard care clinical contacts were: general practitioner (7 visits; 1.2%), community nurse (169; 28.5%), practice nurse visits (189; 31.8%) and dermatology clinic visits (138; 23.2%). Participants whose wounds healed (34 of 45; 75.6%) attended an optional clinic visit. Conclusion: Data were obtained to inform a future RCT. Recruitment rates were found to be higher in centres with dedicated research support. People would be willing to take part in a trial and attend a confirmation of healing visit.
  • Healing of ExcisionAl wounds on Lower legs by Secondary intention (HEALS) cohort study. Part 1: a multicentre prospective observational cohort study in patients without planned compression

    Veitch, David (2022-10)
    Background: There is no agreed treatment pathway following excision of keratinocyte cancer (KC). Compression therapy is considered beneficial for secondary intention healing on the lower leg; however, there is a lack of supportive evidence. To plan a randomized controlled trial (RCT), suitable data are needed. We report a multicentre prospective observational cohort study in this patient population with the intention of informing a future trial design. Aim: To estimate the time to healing in wounds healing by secondary intention without planned postoperative compression, following excision of KC on the lower leg; to characterize the patient population, including factors affecting healing; and to assess the incidence of complications. Methods: This was a multicentre prospective observational cohort study. Inclusion criteria were age ≥ 18 years with planned excision of KC on the lower leg and healing by secondary intention, an ankle-brachial pressure index (ABPI) of ≥ 0.8; and written informed consent. Exclusion criteria included planned excision with primary closure, skin graft or flap; compression therapy for another indication; planned compression; inability of patient to receive, comply with or tolerate high compression; or a suspected diagnosis other than KC. Results: This study recruited 58 patients from 9 secondary care dermatology clinics. In the analysis population (n = 53), mean age was 81 years (range 25-97 years), median time to healing was 81 days (95% CI 73-92) and 45 patients (84.9%) had healing of the wound at the 6-month follow-up. The healing prognostic factors were wound parameters and ABPI. Wound infections occurred in 16 participants (30.2%). Four patients (7.5%) were admitted to hospital; three because of an infection and one because of a fall. Conclusions: The collected data have informed the RCT preparation. A relatively high proportion (7.5-15%) of unhealed wounds, infection and hospital admissions demonstrate the need for clearly establishing potentially effective treatments to improve outcomes for this population.
  • A review of the evidence for Mohs micrographic surgery. Part 2: basal cell carcinoma

    Veitch, David; Wernham, Aaron (2022-10)
    Mohs micrographic surgery (MMS) is considered the gold-standard treatment for basal cell carcinoma (BCC) particularly for sites with a high-risk of incomplete excision such as the central face, for tumours with an aggressive growth pattern and consequent unpredictable subclinical extension and for recurrent tumours. However, the process is more time-consuming than for standard excision (SE), and the magnitude of benefit is uncertain. This article aims to provide a more complete picture of current evidence, including a review of cosmetic outcomes, tissue-sparing ability and cost-effectiveness of MMS. Although robust evidence is lacking, there is a large volume of observational data supporting a low recurrence rate after MMS. The risk of incomplete excision and higher recurrence rate of standard excision favours the use of MMS at high-risk sites. There is some low-certainty evidence that MMS results in a smaller defect size compared with SE, and that incomplete excision with SE results in larger defects. Larger defects may affect cosmetic outcome but there is no direct evidence that MMS improves cosmetic outcome compared with SE. There is conflicting evidence regarding the cost of MMS compared with SE, as some studies consider MMS less expensive than SE and others consider it more expensive, which may reflect the healthcare setting. A multicentre 10-year randomized controlled trial comparing MMS and SE in the treatment of high-risk BCC would be desirable, but is unlikely to be feasible or ethical. Collection of robust registry data capturing both MMS and SE outcomes would provide additional long-term outcomes.
  • A review of Mohs micrographic surgery for skin cancer. Part 3: Squamous cell carcinoma

    Veitch, David; Wernham, Aaron (2022-10)
    This review presents and discusses the evidence for MMS to treat cutaneous squamous cell carcinoma (cSCC). The MEDLINE, Embase and Cochrane databases were searched; 39 papers were identified for recurrence and 2 papers for cost-effectiveness. We included all clinical trials and observational studies, including retrospective reports, and excluded editorials and systematic reviews or meta-analyses. We categorized the evidence under the following headings: tumour recurrence, specific site outcomes (ear, lip, scalp and periocular), cSCC with perineural invasion, and cost-effectiveness. Although there are many observational studies indicating the potential benefits of MMS in the management of certain cSCCs, no randomized controlled trials (RCT) were identified. The evidence from comparitor studies suggests that MMS has a lower recurrence rate than that of other treatments for cSCC, including standard excision. Many studies identified were single-armed, but did demonstrate a low to very low recurrence rate of cSCC following MMS. A single recent study suggests MMS for intermediate cSCC is highly cost-effective compared with wide local excision when all-in costs are considered. Since the overall quality of included studies was mixed and highly heterogeneous, further methodologically robust studies with comparator arms or comprehensive long-term registry data would be valuable. It would be ideal to employ a definitive multicentre RCT but given the evidence to date and multiple advantages to MMS, the lack of clinical equipoise makes this difficult to justify. Comparison with current modalities would likely not be ethical/achievable on a like-for-like basis given MMS provides 100% margin assessment, enables histological clearance prior to reconstruction, and minimizes the removal of uninvolved tissue.
  • Anetumab ravtansine versus vinorelbine in patients with relapsed, mesothelin-positive malignant pleural mesothelioma (ARCS-M): a randomised, open-label phase 2 trial

    Fennell, Dean (2022-04)
    Background: Few treatment options exist for second-line treatment of malignant pleural mesothelioma. We aimed to assess the antibody-drug conjugate anetumab ravtansine versus vinorelbine in patients with unresectable locally advanced or metastatic disease overexpressing mesothelin who had progressed on first-line platinum-pemetrexed chemotherapy with or without bevacizumab. Methods: In this phase 2, randomised, open-label study, done at 76 hospitals in 14 countries, we enrolled adults (aged ≥18 years) with unresectable locally advanced or metastatic malignant pleural mesothelioma, an Eastern Cooperative Oncology Group performance status of 0-1, and who had progressed on first-line platinum-pemetrexed chemotherapy with or without bevacizumab. Participants were prospectively screened for mesothelin overexpression (defined as 2+ or 3+ mesothelin membrane staining intensity on at least 30% of viable tumour cells by immunohistochemistry) and were randomly assigned (2:1), using an interactive voice and web response system provided by the sponsor, to receive intravenous anetumab ravtansine (6·5 mg/kg on day 1 of each 21-day cycle) or intravenous vinorelbine (30 mg/m2 once every week) until progression, toxicity, or death. The primary endpoint was progression-free survival according to blinded central radiology review, assessed in the intention-to-treat population, with safety assessed in all participants who received any study treatment. This study is registered with, NCT02610140, and is now completed. Findings: Between Dec 3, 2015, and May 31, 2017, 589 patients were enrolled and 248 mesothelin-overexpressing patients were randomly allocated to the two treatment groups (166 patients were randomly assigned to receive anetumab ravtansine and 82 patients were randomly assigned to receive vinorelbine). 105 (63%) of 166 patients treated with anetumab ravtansine (median follow-up 4·0 months [IQR 1·4-5·5]) versus 43 (52%) of 82 patients treated with vinorelbine (3·9 months [1·4-5·4]) had disease progression or died (median progression-free survival 4·3 months [95% CI 4·1-5·2] vs 4·5 months [4·1-5·8]; hazard ratio 1·22 [0·85-1·74]; log-rank p=0·86). The most common grade 3 or worse adverse events were neutropenia (one [1%] of 163 patients for anetumab ravtansine vs 28 [39%] of 72 patients for vinorelbine), pneumonia (seven [4%] vs five [7%]), neutrophil count decrease (two [1%] vs 12 [17%]), and dyspnoea (nine [6%] vs three [4%]). Serious drug-related treatment-emergent adverse events occurred in 12 (7%) patients treated with anetumab ravtansine and 11 (15%) patients treated with vinorelbine. Ten (6%) treatment-emergent deaths occurred with anetumab ravtansine: pneumonia (three [2%]), dyspnoea (two [1%]), sepsis (two [1%]), atrial fibrillation (one [1%]), physical deterioration (one [1%]), hepatic failure (one [1%]), mesothelioma (one [1%]), and renal failure (one [1%]; one patient had 3 events). One (1%) treatment-emergent death occurred in the vinorelbine group (pneumonia). Interpretation: Anetumab ravtansine showed a manageable safety profile and was not superior to vinorelbine. Further studies are needed to define active treatments in relapsed mesothelin-expressing malignant pleural mesothelioma. Funding: Bayer Healthcare Pharmaceuticals.
  • Results of a single-arm pilot study of 32 P microparticles in unresectable locally advanced pancreatic adenocarcinoma with gemcitabine/nab-paclitaxel or FOLFIRINOX chemotherapy

    Iwuji, Chinenye (2022-02)
    Background: Unresectable locally advanced pancreatic cancer (LAPC) is generally managed with chemotherapy or chemoradiotherapy, but prognosis is poor with a median survival of ∼13 months (or up to 19 months in some studies). We assessed a novel brachytherapy device, using phosphorous-32 (32P) microparticles, combined with standard-of-care chemotherapy. Patients and methods: In this international, multicentre, single-arm, open-label pilot study, adult patients with histologically or cytologically proven unresectable LAPC received 32P microparticles, via endoscopic ultrasound-guided fine-needle implantation, planned for week 4 of 5-fluorouracil, leucovorin, irinotecan and oxaliplatin (FOLFIRINOX) or gemcitabine/nab-paclitaxel chemotherapy, per investigator's choice. The primary endpoint was safety and tolerability measured using Common Terminology Criteria for Adverse Events version 4.0. The lead efficacy endpoint was local disease control rate at 16 weeks. Results: Fifty patients were enrolled and received chemotherapy [intention-to-treat (ITT) population]. Forty-two patients received 32P microparticle implantation [per protocol (PP) population]. A total of 1102 treatment-emergent adverse events (TEAEs) were reported in the ITT/safety population (956 PP), of which 167 (139 PP) were grade ≥3. In the PP population, 41 TEAEs in 16 (38.1%) patients were possibly or probably related to 32P microparticles or implantation procedure, including 8 grade ≥3 in 3 (7.1%) patients, compared with 609 TEAEs in 42 (100%) patients attributed to chemotherapy, including 67 grade ≥3 in 28 patients (66.7%). The local disease control rate at 16 weeks was 82.0% (95% confidence interval: 68.6% to 90.9%) (ITT) and 90.5% (95% confidence interval: 77.4% to 97.3%) (PP). Tumour volume, carbohydrate antigen 19-9 levels, and metabolic tumour response at week 12 improved significantly. Ten patients (20.0% ITT; 23.8% PP) had surgical resection and median overall survival was 15.2 and 15.5 months for ITT and PP populations, respectively. Conclusions: Endoscopic ultrasound-guided 32P microparticle implantation has an acceptable safety profile. This study also suggests clinically relevant benefits of combining 32P microparticles with standard-of-care systemic chemotherapy for patients with unresectable LAPC.
  • Platelet biomarkers in patients with atherosclerotic extracranial carotid artery stenosis: a systematic review

    Naylor, Ross (2022-03)
    Objective: The aim was to enhance understanding of the role of platelet biomarkers in the pathogenesis of vascular events and risk stratifying patients with asymptomatic or symptomatic atherosclerotic carotid stenosis. Data sources: Systematic review conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. Review methods: A systematic review collated data from 1975 to 2020 on ex vivo platelet activation and platelet function/reactivity in patients with atherosclerotic carotid stenosis. Results: Forty-three studies met the inclusion criteria; the majority included patients on antiplatelet therapy. Five studies showed increased platelet biomarkers in patients with ≥ 30% asymptomatic carotid stenosis (ACS) vs. controls, with one neutral study. Preliminary data from one study suggested that quantification of "coated platelets" in combination with stenosis severity may aid risk stratification in patients with ≥ 50% - 99% ACS. Platelets were excessively activated in patients with ≥ 30% symptomatic carotid stenosis (SCS) vs. controls (≥ 11 positive studies and one neutral study). Antiplatelet-High on Treatment Platelet Reactivity (HTPR), previously called "antiplatelet resistance", was observed in 23% - 57% of patients on aspirin, with clopidogrel-HTPR in 25% - 100% of patients with ≥ 50% - 99% ACS. Aspirin-HTPR was noted in 9.5% - 64% and clopidogrel-HTPR in 0 - 83% of patients with ≥ 50% SCS. However, the data do not currently support the use of ex vivo platelet function/reactivity testing to tailor antiplatelet therapy outside of a research setting. Platelets are excessively activated (n = 5), with increased platelet counts (n = 3) in recently symptomatic vs. asymptomatic patients, including those without micro-emboli on transcranial Doppler (TCD) monitoring (n = 2). Most available studies (n = 7) showed that platelets become more reactive or activated following carotid endarterectomy or stenting, either as an acute phase response to intervention or peri-procedural treatment. Conclusion: Platelets are excessively activated in patients with carotid stenosis vs. controls, in recently symptomatic vs. asymptomatic patients, and may become activated/hyper-reactive following carotid interventions despite commonly prescribed antiplatelet regimens. Further prospective multicentre studies are required to determine whether models combining clinical, neurovascular imaging, and platelet biomarker data can facilitate optimised antiplatelet therapy in individual patients with carotid stenosis.
  • Obinutuzumab as consolidation after chemo-immunotherapy: Results of the UK National Cancer Research Institute phase II/III GALACTIC trial

    Kennedy, Ben (2022-08)
    The GA101 (obinutuzumab) monocLonal Antibody as Consolidation Therapy In chronic lymphocytic leukaemia (CLL) (GALACTIC) was a seamless phase II/III trial designed to test whether consolidation with obinutuzumab is safe and eradicates minimal residual disease (MRD) and, subsequently, whether this leads to prolonged progression-free survival (PFS) in patients with CLL who have recently responded to chemo-immunotherapy. Patients with a response 3-24 months after chemotherapy were assessed for MRD. MRD-positive patients were randomised to receive consolidation therapy with obinutuzumab or no consolidation. The trial closed after the phase II part due to slow recruitment. In all, 48 patients enrolled of whom 19 were MRD negative and were monitored. Of the 29 MRD-positive patients, 14 were randomised to receive consolidation and 15 to no consolidation. At 6 months after randomisation, 10 and 13 consolidated patients achieved MRD negativity by flow cytometry (sensitivity 10-4 ) in bone marrow and peripheral blood respectively. PFS was significantly better in consolidated patients compared to non-consolidated patients (p = 0.001). No difference was observed in PFS, overall survival or duration of MRD negativity when comparing the 10 MRD-negative patients after consolidation with the 19 MRD-negative patients in the monitoring group. Common adverse events in the consolidation arm were thrombocytopenia, infection, and cough. Only 1% of events were infusion-related reactions. This observation provides further evidence that consolidation to achieve MRD negativity improves outcomes in CLL and that obinutuzumab is well tolerated in patients with low levels of disease.
  • Depth of response and response kinetics of isatuximab plus carfilzomib and dexamethasone in relapsed multiple myeloma

    Garg, Mamta (2022-08)
    The IKEMA study (Randomized, Open Label, Multicenter Study Assessing the Clinical Benefit of Isatuximab Combined With Carfilzomib [Kyprolis®] and Dexamethasone Versus Carfilzomib With Dexamethasone in Patients With Relapse and/or Refractory Multiple Myeloma Previously Treated With 1 to 3 Prior Lines; #NCT03275285) was a randomized, open-label, multicenter phase 3 study investigating isatuximab plus carfilzomib and dexamethasone (Isa-Kd) vs Kd in patients with relapsed multiple myeloma. This subanalysis analyzed the depth of response of Isa-Kd vs Kd. The primary end point was progression-free survival (PFS); secondary end points included overall response rate, very good partial response or better (≥VGPR) rate, complete response (CR) rate, and minimal residual disease (MRD) negativity rate (assessed in patients with ≥VGPR by next-generation sequencing at a 10-5 sensitivity level). At a median follow-up of 20.7 months, deeper responses were observed in the Isa-Kd arm vs the Kd arm, with ≥VGPR 72.6% vs 56.1% and CR of 39.7% vs 27.6%, respectively. MRD negativity occurred in 53 (29.6%) of 179 patients in the Isa-Kd arm vs 16 (13.0%) of 123 patients in the Kd arm, with 20.1% (Isa-Kd, 36 of 179 patients) vs 10.6% (Kd, 13 of 123 patients) reaching MRD-negative CR status. Achieving MRD negativity resulted in better PFS in both arms. A positive PFS treatment effect was seen with Isa-Kd in both MRD-negative patients (hazard ratio, 0.578; 95% CI, 0.052-6.405) and MRD-positive patients (hazard ratio, 0.670; 95% CI, 0.452-0.993). Exploratory analysis indicates that both current CR and MRD-negative CR rates are underestimated due to M-protein interference (potential adjusted CR rate, 45.8%; potential adjusted MRD-negative CR rate, 24.0%). In conclusion, there was a clinically meaningful improvement in depth of response with Isa-Kd. The CR rate in Isa-Kd was 39.7%. Mass spectrometry suggests that the potential adjusted CR rate could reach an unprecedented 45.8% of patients treated with Isa-Kd.
  • Mast cell activation syndrome and the link with long COVID

    Myers, Bethan (2022-07)
    Mast cells are innate immune cells found in connective tissues throughout the body, most prevalent at tissue-environment interfaces. They possess multiple cell-surface receptors which react to various stimuli and, after activation, release many mediators including histamine, heparin, cytokines, prostaglandins, leukotrienes and proteases. In mast cell activation syndrome, excessive amounts of inflammatory mediators are released in response to triggers such as foods, fragrances, stress, exercise, medications or temperature changes. Diagnostic markers may be difficult to assess because of their rapid degradation; these include urinary N-methyl histamine, urinary prostaglandins D2, DM and F2α and serum tryptase (which is stable) in the UK. Self-management techniques, medications and avoiding triggers may improve quality of life. Treatments include mast cell mediator blockers, mast cell stabilisers and anti-inflammatory agents. 'Long COVID' describes post-COVID-19 syndrome when symptoms persist for more than 12 weeks after initial infection with no alternative diagnosis. Both mast cell activation syndrome and long COVID cause multiple symptoms. It is theorised that COVID-19 infection could lead to exaggeration of existing undiagnosed mast cell activation syndrome, or could activate normal mast cells owing to the persistence of viral particles. Other similarities include the relapse-remission cycle and improvements with similar treatments. Importantly, however, aside from mast cell disorders, long COVID could potentially be attributed to several other conditions.

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