Tumor characteristics of dissociated response to immune checkpoint inhibition in advanced melanoma.

INTRODUCTION: Immune checkpoint inhibition (ICI) has improved patients' outcomes in advanced melanoma, often resulting in durable response. However, not all patients have durable responses and the patients with dissociated response are a valuable subgroup to identify mechanisms of ICI resistance. METHODS: Stage IV melanoma patients treated with ICI and dissociated response were retrospectively screened for available samples containing sufficient tumor at least at two time-points. Included were one patient with metachronous regressive and progressive lesions at the same site, two patients with regressive and novel lesion at different sites, and three patients with regressive and progressive lesions at different sites. In addition, four patients with acquired resistant tumor samples without a matched second sample were included. RESULTS: In the majority of patients, the progressive tumor lesion contained higher CD8+ T cell counts/mm2 and interferon-gamma (IFNγ) signature level, but similar tumor PD-L1 expression. The tumor mutational burden levels were in 2 out 3 lesions higher compared to the corresponding regressive tumors lesion. In the acquired tumor lesions, high CD8+/mm2 and relatively high IFNγ signature levels were observed. In one patient in both the B2M and PTEN gene a stop gaining mutation and in another patient a pathogenic POLE mutation were found. CONCLUSION: Intrapatient comparison of progressive versus regressive lesions indicates no defect in tumor T cell infiltration, and in general no tumor immune exclusion were observed.

Indeterminate thyroid nodules (Thy3): malignancy rate and characteristics in a study of 118 patients.

INTRODUCTION: Thyroid nodules are common, and the combined use of ultrasound and fine needle aspiration cytology provides useful information on their malignancy risk. The Thy reporting system is widely used in the United Kingdom, with malignancy rates for Thy3 cytology being quoted between 5% and 30%. This study aims to establish the risk of thyroid cancer in operated patients with Thy3 cytology and correlate it with patient demographics and nodule size. METHODS: This is a retrospective observational study of all thyroidectomies that took place in a single institution over a 3-year period (2019-2022). Those with a preoperative cytology of Thy3 were analysed further and in particular, nodule size, final histology and patients' demographics were documented. RESULTS: Some 260 thyroidectomies were performed during the study period. Of these, 118 patients had Thy3 cytology. In the Thy3a group (n = 70), the malignancy rate was 27.1%. The average age of those with thyroid cancer was 51.4 vs 51.2 years for those with benign disease. The nodule size was under 40mm for both groups (36mm vs 39.7mm). In the Thy3f group (n = 48), the malignancy rate was 43.8%. The average age of those with thyroid cancer was 53.5 vs 56.2 years for those with benign disease. The nodule size was similar (24.5mm vs 27.6mm). CONCLUSIONS: In this study, one in three patients with Thy3 cytology was diagnosed with thyroid cancer. We urge local units to analyse their data, to aid patients' informed decision-making. Within the subgroups, there was no significant difference in average nodule size or patients' age.

Inhibitor of Apoptosis Proteins Antagonist Induces T-cell Proliferation after Cross-Presentation by Dendritic Cells.

Cross-presentation of tumor antigens by dendritic cells (DC) is crucial to prime, stimulate and restimulate CD8+ T cells. This process is important in initiating and maintaining an antitumor response. Here, we show that the presence of conventional type 1 DCs (cDC1), a DC subtype that excels in cross-presentation, in the tumor correlated with response to neoadjuvant immune checkpoint blockade (ICB) in melanoma. This led us to hypothesize that patients failing to respond to ICB could benefit from enhanced cross-presentation of tumor antigens. We therefore established a cross-presentation assay to screen over 5,500 compounds for enhancers of DC cross-presentation using induced T-cell proliferation as the readout. We identified 145 enhancers, including AZD5582, an antagonist of inhibitor of apoptosis proteins (IAP) cIAP1, cIAP2, and XIAP. AZD5582 treatment led to DC activation of the noncanonical NF-kB pathway, enhanced antigen import from endolysosomes into the cytosol, and increased expression of genes involved in cross-presentation. Furthermore, it upregulated expression of CD80, CD86, MHC class II, CD70 and secretion of TNF by DCs. This enhanced DC activation and maturation program was observed also in tumor-bearing mice upon AZD5582 treatment, culminating in an increased frequency of systemic tumor antigen-specific CD8+ T cells. Our results merit further exploration of AZD5582 to increase antigen cross-presentation for improving the clinical benefit of ICB in patients who are unlikely to respond to ICB.

Age-related hearing loss and mild cognitive impairment: a meta-analysis and systematic review of population-based studies.

BACKGROUND: The aim of this study was to identify any relationship between hearing loss and mild cognitive impairment. METHOD: This was a systematic review and meta-analysis of randomised controlled trials conducted using Medline and the Cochrane Library up to 24 June 2020. Prospective, cohort and cross-sectional, and observational studies that reported on the relationship between mild cognitive impairment and hearing loss were included. RESULTS: A total of 34 studies reporting data on 48 017 participants were included. Twenty-three studies observed a significant association between hearing loss and mild cognitive impairment. The pooled risk ratio across all studies of prevalence of mild cognitive impairment in people with hearing loss was 1.44 (random-effects; 95 per cent CI = 1.27-1.64; p < 0.00001; I2 = 0 per cent). Significantly more people with mild cognitive impairment had peripheral hearing loss compared with those without (risk ratio, 1.40 random-effects; 95 per cent CI = 1.10-1.77; p = 0.005; I2 = 0 per cent). When the incidence was studied, significantly more people with peripheral hearing loss had mild cognitive impairment compared with those without (risk ratio = 2.06 random-effects; 95 per cent CI = 1.35-3.15; p = 0.0008; I2 = 97 per cent); however; a high level of statistical heterogeneity was evident. CONCLUSION: Most of the studies included in this systematic review observed a significant association between hearing loss and mild cognitive impairment.

Survival and biomarker analyses from the OpACIN-neo and OpACIN neoadjuvant immunotherapy trials in stage III melanoma.

Neoadjuvant ipilimumab plus nivolumab showed high pathologic response rates (pRRs) in patients with macroscopic stage III melanoma in the phase 1b OpACIN ( NCT02437279 ) and phase 2 OpACIN-neo ( NCT02977052 ) studies1,2. While the results are promising, data on the durability of these pathologic responses and baseline biomarkers for response and survival were lacking. After a median follow-up of 4 years, none of the patients with a pathologic response (n = 7/9 patients) in the OpACIN study had relapsed. In OpACIN-neo (n = 86), the 2-year estimated relapse-free survival was 84% for all patients, 97% for patients achieving a pathologic response and 36% for nonresponders (P < 0.001). High tumor mutational burden (TMB) and high interferon-gamma-related gene expression signature score (IFN-γ score) were associated with pathologic response and low risk of relapse; pRR was 100% in patients with high IFN-γ score/high TMB; patients with high IFN-γ score/low TMB or low IFN-γ score/high TMB had pRRs of 91% and 88%; while patients with low IFN-γ score/low TMB had a pRR of only 39%. These data demonstrate long-term benefit in patients with a pathologic response and show the predictive potential of TMB and IFN-γ score. Our findings provide a strong rationale for a randomized phase 3 study comparing neoadjuvant ipilimumab plus nivolumab versus standard adjuvant therapy with antibodies against the programmed cell death protein-1 (anti-PD-1) in macroscopic stage III melanoma.

Surgical and functional outcomes of two types of transcutaneous bone conduction implants.

OBJECTIVE: This study aimed to evaluate surgical and functional outcomes, in a tertiary referral centre, of two different types of semi-implantable transcutaneous bone conduction devices. METHOD: This study involved prospective data collection and review of patients implanted between November 2014 and December 2016. Glasgow Hearing Aid Inventory (Glasgow Hearing Aid Benefit Profile or Glasgow Hearing Aid Difference Profile) and Client Oriented Scale of Improvement were completed where appropriate. Surgical and audiological outcomes were recorded in the surgical notes. RESULTS: Glasgow Hearing Aid Difference Profile and Glasgow Hearing Aid Benefit Profile showed similar mean score in the active and the passive transcutaneous bone conduction devices. Client Oriented Scale of Improvement showed improvements in listening situations. Post-operative speech reception threshold showed better mean threshold in the active transcutaneous bone conduction devices group when compared with the passive transcutaneous bone conduction devices group. No device failures or surgical complications existed in either group, with the surgical time being less in the passive transcutaneous bone conduction devices group. CONCLUSION: Both devices are reliable semi-implantable transcutaneous bone conduction devices with excellent surgical and functional outcomes and patient satisfaction. Overall surgical time was much less in the passive transcutaneous bone conduction devices group with no necessity for pre-planning. This is much easier to remove with the possibility of conversion to other devices in the manufacturer's portfolio and wide-ranging wireless accessories. Further studies are needed to assess the longer-term results in a bigger population.

Soft-tissue outcomes following implantation of different types of bone conduction hearing devices in a single centre.

OBJECTIVE: To compare soft-tissue complications following implantation of different bone conduction hearing devices. METHODS: Adults who underwent implantation of different bone conduction hearing devices, between January 2008 and December 2016, were included in the study. Five groups were identified depending on the soft-tissue approach: (1) split-thickness skin flap with use of dermatome; (2) Sheffield 'S'-shaped incision with skin thinning; (3) linear incision without skin thinning (hydroxyapatite-coated abutment); (4) 'C'-shaped full-thickness incision for passive transcutaneous bone conduction hearing devices; and (5) post-aural incision for active transcutaneous bone conduction hearing devices. The main outcome measures were different soft-tissue complications. RESULTS: The study comprised 120 patients (group 1 = 20 patients, group 2 = 35, group 3 = 35, group 4 = 20, and group 5 = 10). Soft tissue related problems were encountered in 55 per cent of patients from group 1, 26 per cent in group 2, 3 per cent in group 3, and 0 per cent in groups 4 and 5. CONCLUSION: There was a reduction in soft tissue related complications with reduced soft-tissue handling. In addition, there was a shift from an initial skin-penetrating (percutaneous) approach to a non-skin-penetrating (transcutaneous) approach.

White matter lesions in magnetic resonance imaging of the brain in 56 patients with visual vertigo.

BACKGROUND: Visual vertigo is defined as a condition in which there is worsening or triggering of vestibular symptoms in certain visual environments. Previous studies have associated visual vertigo with an increased prevalence of underlying white matter lesions on brain imaging. METHOD: This study evaluated the magnetic resonance imaging scans of the brain from a cohort of patients with visual vertigo, and compared the outcomes to an age- and gender-matched group of healthy volunteers.Results and conclusionWhite matter lesions were observed in 17.9 per cent of the patient group and in 16.3 per cent of the control group. The prevalence of white matter lesions in the patient group was not too different to that expected based on age.

The use of FloSeal haemostatic sealant in the management of epistaxis: a prospective clinical study and literature review.

INTRODUCTION It is standard practice in the UK that if conservative measures or chemical cautery fail to control epistaxis, patients receive nasal packing which is often uncomfortable, requires admission and has well documented associated morbidity. Our study aims to evaluate the use of FloSeal haemostatic sealant in managing patients with epistaxis. MATERIALS AND METHODS Patients were identified from those referred with active epistaxis. A successful outcome was defined as complete haemostasis with FloSeal alone, with no further significant bleeding requiring admission or further interventions in the subsequent 7 days. Patients reported satisfaction using a ten-point visual analogue scale. Ear, nose and throat doctors recorded patient demographics, time to prepare FloSeal, length of stay, need for further treatment and adverse events on an electronic database. RESULTS 30 patients were enrolled in the study. The mean time to prepare FloSeal was 5 minutes. The success rate of FloSeal was 90%. The mean length of stay was 2.75 hours. The mean patient satisfaction with FloSeal was 8.4/10. No adverse events occurred. DISCUSSION FloSeal was found to be effective in controlling anterior epistaxis. There was a single case of posterior epistaxis which required operative management. The literature largely supports FloSeal in anterior epistaxis, but indicates sphenopalatine artery ligation as the definitive management of posterior epistaxis. CONCLUSIONS Our data support the use of FloSeal in patients with anterior epistaxis not controlled with conservative measures or chemical cautery. It was found to be easy to use, is well tolerated by patients and is efficient in financial terms.

The role of acetic acid on glucose uptake and blood flow rates in the skeletal muscle in humans with impaired glucose tolerance.

BACKGROUND/OBJECTIVES: Previous studies support the glucose-lowering effect of vinegar. However, the effect of vinegar on muscle glucose metabolism and endothelial function has not been studied in humans. This open, randomized, crossover, placebo-controlled study aims to investigate the effects of vinegar on muscle glucose metabolism, endothelial function and circulating lipid levels in subjects with impaired glucose tolerance (IGT) using the arteriovenous difference technique. SUBJECTS/METHODS: Eight subjects with IGT (4 males, age 46±10 years, body mass index 30±5) were randomised to consume 0.50 mmol vinegar (6% acetic acid) or placebo before a mixed meal. Plasma samples were taken for 300 min from the radial artery and the forearm vein for measurements of glucose, insulin, triglycerides, non-esterified fatty acids (NEFAs) and glycerol. Muscle blood flow was measured with strain gauge plethysmography. Glucose flux was calculated as the arteriovenous difference of glucose multiplied by the blood flow rates. RESULTS: Vinegar compared with placebo: (1) decreased arterial plasma insulin (Poverall<0.001; P75 min=0.014, ß=-42), (2) increased forearm blood flow (Poverall<0.001; P240 min=0.011, ß=1.53; P300 min=0.023, ß=1.37), (3) increased muscle glucose uptake (Poverall<0.001; P60 min=0.029, ß=2.78) and (4) decreased arterial plasma triglycerides (Poverall=0.005; P240 min<0.001, ß=-344; P300 min<0.001, ß=-373), without changing NEFA and glycerol. CONCLUSIONS: In individuals with IGT, vinegar ingestion before a mixed meal results in an enhancement of muscle blood flow, an improvement of glucose uptake by the forearm muscle and a reduction of postprandial hyperinsulinaemia and hypertriglyceridaemia. From this point of view, vinegar may be considered beneficial for improving insulin resistance and metabolic abnormalities in the atherogenic prediabetic state.

The challenge of cancellations on the day of surgery.

INTRODUCTION: Cancellations of planned surgical procedures have been a major and long-standing problem for healthcare organisations across the world. They represent a significant loss of revenue and waste of resources, have significant psychological, social and financial implications for patients and their families and represent a significant loss of training opportunities for surgical trainees. The current study investigates the reasons for day of surgery cancellations at an NHS Foundation Trust in the United Kingdom and proposes strategies to reduce their incidence. METHODS: All cancellations of elective and emergency procedures during the period from January 2012 to December 2012 were identified retrospectively using the IQ Utopia patient management software. RESULTS: The rate of cancellations on the day of surgery for elective and planned emergency procedures during 2012 was 5.19%. The main reason for cancellation was patient not fit for operation (33.73%), followed by lack of beds (21.79%), lack of theatre time (17.31%), patient failed to attend (6.87%) and operation no longer necessary (4.08%). CONCLUSIONS: Similar reasons for cancellations have been reported in studies from around the world. The published literature provides various examples of successful and unsuccessful strategies to reduce surgery cancellations, even when they are caused by factors that are sometimes considered unavoidable. The feasibility and profitability of approaches that have been proven to be successful in other institutions should be assessed thoroughly in the context of the individual institution's characteristics and individual problems before a decision for implementation is made.

'Crohn'z meanz Heinz': foreign body inflammatory mass mimicking Crohn's disease.

The authors present a patient with a presumed diagnosis of Crohn's disease for 6 years turning out to be an unusual inflammatory mass caused by ileal perforation due to a foreign body. When surgical intervention became necessary for admissions with recurrent obstruction, laparoscopy revealed an inflammatory mass in the terminal ileum, exposing two pieces of plastic bearing the word 'Heinz'. Resection of the inflammatory mass led to the complete resolution of symptoms. Histology from the operative specimen showed no features of Crohn's disease. There were no granulomas and no fissuring ulcers. This case highlights that an inflammatory mass in the small intestine caused by the perforation of ingested foreign body can mimic Crohn's disease. To our knowledge, this is the first report of a synthetic plastic packaging causing ileo-caecal junctional perforation mimicking Crohn's disease.

Superglue ear: our experience and a review of the literature.

Cyanoacrylate glue (Superglue) has the ability to bond a variety of surfaces firmly within seconds of use. Its application into the external ear canal (EAC) is a challenging problem for clinicians. We present 3 case reports of patients who presented at our hospital with superglue in their EACs: 1 was accidental, 1 was iatrogenic, and 1 was intentional. To our knowledge, iatrogenic application of cyanoacrylate glue to the EAC has not been reported previously. We describe our management of these cases and review similar cases reported in the literature. These cases highlight the pressing need for changes in the size, shape and colour of the containers to make them more easily recognizable and distinctive.

The Gm and Inv factors in rheumatoid arthritis.

The Gm(1), Gm(2), Gm(4), Gm(12), and Inv (1) factors were studied in the sera of 56 patients suffering from rheumatiod arthritis and 26 from various rheumatic diseases, by the hemagglutination inhibition test, using optimally reacting mixtures of Ragg and Nagg sera. The distribution of these factors was found to agree with that of healthy Greeks. No correlation was found between hypergammaglobulinemia and the discovery of the Gm(1) and Inv (1) factors. The presence of the rheumatoid factor was independent of the Gm and Inv phenotypes.