Management Approaches in WHO Grade III Meningioma: A National Oncology Trainees' Collaborative for Healthcare Research (NOTCH) UK Multi-Centre Retrospective Study.

AIMS: WHO Grade 3 (G3) meningiomas are rare tumours with limited data to guide management. This retrospective study documents UK management approaches across 14 centres over 11 years. MATERIALS AND METHODS: Patients with WHO G3 meningioma between 01/01/2008 and 31/12/2018 were identified. Data were collected on demographics, management strategy, adjuvant radiotherapy, approach in recurrence setting and survival. RESULTS: 84 patients were identified. 21.4% transformed from lower-grade disease. 96.4% underwent primary surgical resection, with 20.8% having evidence of residual disease on their post-op MRI. 59.3% of patients underwent adjuvant radiotherapy (RT) following surgical resection. Overall median PFS and OS were 12.6 months and 28.2 months, respectively. Median OS in the group who underwent complete surgical resection was 34.9 months, compared to 27.5 months for those who had incomplete resection (HR 0.58, 95% CI 0.27-1.23, p = 0.15). Median OS was 33.1 months for those who underwent adjuvant RT and 14.0 months for those who did not (HR 0.48, 95% CI 0.27-0.84, p = 0.004). Median adjuvant RT dose delivered was 60Gy (range 12Gy-60Gy), 45.8% of adjuvant RT was delivered using IMRT. At disease relapse, 31% underwent salvage surgery and 29.3% underwent salvage RT. Of those treated with salvage RT, 64.7% were re-treats and all were treated with hypofractionated RT. CONCLUSION: Surgery continues to be the preferred primary management strategy. Post-operative MRI within 48 hours is indicated to assess presence of residual disease and guide further surgical options. Adjuvant radiotherapy plays an important part of the management paradigm in these patients with the data supporting an attached survival advantage. Further surgery and re-irradiation is an option in the disease recurrence setting with radiosurgery frequently utilised in this context.

An investigation of the clinical impact and therapeutic relevance of a DNA damage immune response (DDIR) signature in patients with advanced gastroesophageal adenocarcinoma.

BACKGROUND: An improved understanding of which gastroesophageal adenocarcinoma (GOA) patients respond to both chemotherapy and immune checkpoint inhibitors (ICI) is needed. We investigated the predictive role and underlying biology of a 44-gene DNA damage immune response (DDIR) signature in patients with advanced GOA. MATERIALS AND METHODS: Transcriptional profiling was carried out on pretreatment tissue from 252 GOA patients treated with platinum-based chemotherapy (three dose levels) within the randomized phase III GO2 trial. Cross-validation was carried out in two independent GOA cohorts with transcriptional profiling, immune cell immunohistochemistry and epidermal growth factor receptor (EGFR) fluorescent in situ hybridization (FISH) (n = 430). RESULTS: In the GO2 trial, DDIR-positive tumours had a greater radiological response (51.7% versus 28.5%, P = 0.022) and improved overall survival in a dose-dependent manner (P = 0.028). DDIR positivity was associated with a pretreatment inflamed tumour microenvironment (TME) and increased expression of biomarkers associated with ICI response such as CD274 (programmed death-ligand 1, PD-L1) and a microsatellite instability RNA signature. Consensus pathway analysis identified EGFR as a potential key determinant of the DDIR signature. EGFR amplification was associated with DDIR negativity and an immune cold TME. CONCLUSIONS: Our results indicate the importance of the GOA TME in chemotherapy response, its relationship to DNA damage repair and EGFR as a targetable driver of an immune cold TME. Chemotherapy-sensitive inflamed GOAs could benefit from ICI delivered in combination with standard chemotherapy. Combining EGFR inhibitors and ICIs warrants further investigation in patients with EGFR-amplified tumours.

CAnceR IN PreGnancy (CARING) - a retrospective study of cancer diagnosed during pregnancy in the United Kingdom.

BACKGROUND: The incidence of cancer diagnosed during pregnancy is increasing. Data relating to investigation and management, as well as maternal and foetal outcomes is lacking in a United Kingdom (UK) population. METHODS: In this retrospective study we report data from 119 patients diagnosed with cancer during pregnancy from 14 cancer centres in the UK across a five-year period (2016-2020). RESULTS: Median age at diagnosis was 33 years, with breast, skin and haematological the most common primary sites. The majority of cases were new diagnoses (109 patients, 91.6%). Most patients were treated with radical intent (96 patients, 80.7%), however, gastrointestinal cancers were associated with a high rate of palliative intent treatment (63.6%). Intervention was commenced during pregnancy in 68 (57.1%) patients; 44 (37%) had surgery and 31 (26.1%) received chemotherapy. Live births occurred in 98 (81.7%) of the cases, with 54 (55.1%) of these delivered by caesarean section. Maternal mortality during the study period was 20.2%. CONCLUSIONS: This is the first pan-tumour report of diagnosis, management and outcomes of cancer diagnosed during pregnancy in the UK. Our findings demonstrate proof of concept that data collection is feasible and highlight the need for further research in this cohort of patients.

Moving towards a standardized definition of antimicrobial resistance: a comparison of the antimicrobial susceptibility profile of difficult-to-treat resistance (DTR) versus multidrug-resistant (MDR) Pseudomonas aeruginosa clinical isolates (CANWARD, 2016-2021).

Pseudomonas aeruginosa clinical isolates demonstrating difficult-to-treat resistance (DTR) and multidrug-resistant (MDR) phenotypes were evaluated by broth microdilution. Susceptibility was lower for all antimicrobials versus DTR relative to MDR isolates. Ceftazidime-avibactam, ceftolozane-tazobactam, and imipenem-relebactam susceptibility was 35.9%, 64.5%, and 47.0% for DTR isolates and 60.5%, 80.6%, and 71.5% for MDR isolates.

Biomarkers of systemic inflammation predict survival with first-line immune checkpoint inhibitors in non-small-cell lung cancer.

INTRODUCTION: Pembrolizumab is an established first-line option for patients with advanced non-small-cell lung cancer (NSCLC) expressing programmed death-ligand 1 ≥50%. Durable responses are seen in a subset of patients; however, many derive little clinical benefit. Biomarkers of the systemic inflammatory response predict survival in NSCLC. We evaluated their prognostic significance in patients receiving first-line pembrolizumab for advanced NSCLC. METHODS: Patients treated with first-line pembrolizumab for advanced NSCLC with programmed death-ligand 1 expression ≥50% at two regional Scottish cancer centres were identified. Pretreatment inflammatory biomarkers (white cell count, neutrophil count, neutrophil/lymphocyte ratio, platelet/lymphocyte ratio, albumin, prognostic nutritional index) were recorded. The relationship between these and progression-free survival (PFS) and overall survival (OS) were examined. RESULTS: Data were available for 219 patients. On multivariate analysis, albumin and neutrophil count were independently associated with PFS (P < 0.001, P = 0.002, respectively) and OS (both P < 0.001). A simple score combining these biomarkers was explored. The Scottish Inflammatory Prognostic Score (SIPS) assigned 1 point each for albumin <35 g/l and neutrophil count >7.5 × 109/l to give a three-tier categorical score. SIPS predicted PFS [hazard ratio 2.06, 95% confidence interval (CI) 1.68-2.52 (P < 0.001)] and OS [hazard ratio 2.33, 95% CI 1.86-2.92 (P < 0.001)]. It stratified PFS from 2.5 (SIPS2), to 8.7 (SIPS1) to 17.9 months (SIPS0) (P < 0.001) and OS from 5.1 (SIPS2), to 12.4 (SIPS1) to 28.7 months (SIPS0) (P < 0.001). The relative risk of death before 6 months was 2.96 (95% CI 1.98-4.42) in patients with SIPS2 compared with those with SIPS0-1 (P < 0.001). CONCLUSIONS: SIPS, a simple score combining albumin and neutrophil count, predicts survival in patients with NSCLC receiving first-line pembrolizumab. Unlike many proposed prognostic scores, SIPS uses only routinely collected pretreatment test results and provides a categorical score. It stratifies survival across clinically meaningful time periods that may assist clinicians and patients with treatment decisions. We advocate validation of the prognostic utility of SIPS in this and other immune checkpoint inhibitor treatment settings.

Pathophysiology and treatment of osteoporosis: challenges for clinical practice in older people.

Osteoporosis, a common chronic metabolic bone disease is associated with considerable morbidity and mortality. As the prevalence of osteoporosis increases with age, a paralleled elevation in the rate of incident fragility fractures will be observed. This narrative review explores the origins of bone and considers physiological mechanisms involved in bone homeostasis relevant to management and treatment. Secondary causes of osteoporosis, as well as osteosarcopenia are discussed followed by an overview of the commonly used pharmacological treatments for osteoporosis in older people.

Longitudinal characterisation of haematological and biochemical parameters in cancer patients prior to and during COVID-19 reveals features associated with outcome.

BACKGROUND: Cancer patients are at increased risk of death from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Cancer and its treatment affect many haematological and biochemical parameters, therefore we analysed these prior to and during coronavirus disease 2019 (COVID-19) and correlated them with outcome. PATIENTS AND METHODS: Consecutive patients with cancer testing positive for SARS-CoV-2 in centres throughout the United Kingdom were identified and entered into a database following local governance approval. Clinical and longitudinal laboratory data were extracted from patient records. Data were analysed using Mann-Whitney U test, Fisher's exact test, Wilcoxon signed rank test, logistic regression, or linear regression for outcomes. Hierarchical clustering of heatmaps was performed using Ward's method. RESULTS: In total, 302 patients were included in three cohorts: Manchester (n = 67), Liverpool (n = 62), and UK (n = 173). In the entire cohort (N = 302), median age was 69 (range 19-93 years), including 163 males and 139 females; of these, 216 were diagnosed with a solid tumour and 86 with a haematological cancer. Preinfection lymphopaenia, neutropaenia and lactate dehydrogenase (LDH) were not associated with oxygen requirement (O2) or death. Lymphocyte count (P < 0.001), platelet count (P = 0.03), LDH (P < 0.0001) and albumin (P < 0.0001) significantly changed from preinfection to during infection. High rather than low neutrophils at day 0 (P = 0.007), higher maximal neutrophils during COVID-19 (P = 0.026) and higher neutrophil-to-lymphocyte ratio (NLR; P = 0.01) were associated with death. In multivariable analysis, age (P = 0.002), haematological cancer (P = 0.034), C-reactive protein (P = 0.004), NLR (P = 0.036) and albumin (P = 0.02) at day 0 were significant predictors of death. In the Manchester/Liverpool cohort 30 patients have restarted therapy following COVID-19, with no additional complications requiring readmission. CONCLUSION: Preinfection biochemical/haematological parameters were not associated with worse outcome in cancer patients. Restarting treatment following COVID-19 was not associated with additional complications. Neutropaenia due to cancer/treatment is not associated with COVID-19 mortality. Cancer therapy, particularly in patients with solid tumours, need not be delayed or omitted due to concerns that treatment itself increases COVID-19 severity.

Point prevalence of penicillin allergy in hospital inpatients.

Ten percent of the general population believe themselves to be allergic to beta-lactams, many erroneously. Alternative, broader-spectrum antibiotics are associated with increased drug costs and colonization with resistant organisms. A point prevalence study of hospital inpatients determined the local reported rate of penicillin allergy, the nature of allergy described, evidence of antimicrobial resistance and antimicrobial regimens used as a result. Of the 583 patients assessed, the overall rate of penicillin allergy was 13.7% [95% confidence interval (CI) 11-17%]. Rash was the most commonly reported reaction (27.5%, 95% CI 18-39%). Details of the nature of the penicillin allergy were poorly recorded on drug charts. Significantly higher rates of meticillin-resistant Staphylococcus aureus were seen in the allergic cohort (P=0.0065) compared with those without a label of penicillin allergy; this was also seen for vancomycin-resistant enterococci, but this did not reach significance. This study demonstrates an increase in detection of resistant organisms in penicillin-allergic patients which may result from use of broader-spectrum antibiotics in this group.

Influential factors on the composition of the conventionally raised broiler gastrointestinal microbiomes.

The microbiome has entered the vernacular of the consumer as well as broiler production and is, therefore, becoming increasingly important to poultry producers to understand. The microbiome is, by definition, compositional and relates to how the microbiological organisms within the gut inhabit that ecological niche. The gut is diverse, flexible, and data acquired requires a greater understanding of the host-microbiome axes, as well as advanced bioinformatics and ecology. There are numerous microbial populations that define the gut microbiome; however, there are even more effects that can influence its composition. As management practices vary between producers, documenting these influences is an essential component of beginning to understand the microbiome. This review targets broiler production and concatenates the currently understood compositional ecology of the broiler gastrointestinal tract microbiome as well as its influences.

A review of the NG17 recommendations for the use of basal insulin in type 1 diabetes.

AIMS: To revisit the data analysis used to inform National Institute of Health and Care Excellence (NICE) NG17 guidance for initiating basal insulin in adults with type 1 diabetes mellitus (diabetes). METHODS: We replicated the data, methodology and analysis used by NICE diabetes in the NG17 network meta-analysis (NMA). We expanded this data cohort to a more contemporary data set (extended 2017 NMA) and restricted the studies included to improve the robustness of the data set (restricted 2017 NMA) and in a post hoc analysis, changed the index comparator from neutral protamine Hagedorn (NPH) insulin twice daily to insulin detemir twice daily. RESULTS: The absolute changes in HbA1c were similar to those reported in the NG17. However, all 95% credible intervals for change in HbA1c point estimates crossed the line of null effect, except for detemir twice daily (in the NICE and extended 2017 NMAs) and NPH four times daily. In the detemir twice-daily centred post hoc analysis, the 95% credible intervals for change in HbA1c crossed the line of null effect for all basal therapies, except NPH. CONCLUSIONS: In NG17, comparisons of basal insulins were based solely on efficacy of glycaemic control. Many of the trials used in this analysis were treat-to-target, which minimize differences in HbA1c . In the NMAs, statistical significance was severely undermined by the wide credible intervals. Despite these limitations, point estimates of HbA1c were used to rank the insulins and formed the basis of NG17 guidance. This study queries whether such analyses should be used to make specific clinical recommendations.

Metastatic seminoma with isolated gastric metastases: a case report.

Gastric metastases are a rare occurrence in patients with malignancy. In case reports of these arising from germ cell tumours, the majority were non-seminomatous germ cell tumours and had evidence of retroperitoneal involvement. We present a unique case of a 67-year-old man with metastatic testicular pure seminoma. He presented with dyspepsia and investigation found isolated metastases to the gastric mucosa and sub-mucosa from a right testicular primary. No lymph node involvement was identified. The patient was managed with curative intent with total gastrectomy and inguinal orchidectomy. To date, there is no evidence of disease recurrence.

Guidelines for the peri-operative care of people with dementia: Guidelines from the Association of Anaesthetists.

Ageing populations have greater incidences of dementia. People with dementia present for emergency and, increasingly, elective surgery, but are poorly served by the lack of available guidance on their peri-operative management, particularly relating to pharmacological, medico-legal, environmental and attitudinal considerations. These guidelines seek to deliver such guidance, by providing information for peri-operative care providers about dementia pathophysiology, specific difficulties anaesthetising patients with dementia, medication interactions, organisational and medico-legal factors, pre-, intra- and postoperative care considerations, training, sources of further information and care quality improvement tools.

Play behaviour, fear responses and activity levels in commercial broiler chickens provided with preferred environmental enrichments.

There is currently a lack of research investigating the effectiveness of commercial broiler enrichments, and in particular the ability of these additions to create opportunities for positive welfare. One aim of this study was to investigate whether offering broiler chickens enrichments that have recently been found to be preferred leads to increased levels of activity. A second aim was to investigate the emotional effects of provision of these enrichments by assessing levels of fearfulness and play-like activity. Commercially housed broilers were assigned to treatment houses containing either: (1) platform perches, (2) platform perches+peat dust baths, (3) no enrichment (control). Activity levels and play behaviours in unenriched areas of the house were measured in weeks 3, 4 and 5. Levels of active behaviours, such as foraging and locomotion, were determined from video recordings of undisturbed birds in unenriched areas of the house. To stimulate play-like behaviours an observer walked through the birds, displacing them and creating a space. The broilers using the space were then filmed for 5 min and the occurrences of frolicking, sparring and food-running were recorded. Fearfulness of broilers in unenriched areas of the house, and also when using enrichments, was measured using observer avoidance tests in week 5. We found that creating space among the broilers was a successful method of stimulating play (largely sparring and frolicking), with play being observed in 93% of videos, however the presence of enrichments did not have an effect on the level of play recorded (P>0.05). There was also no treatment effect on activity levels of broilers in unenriched areas (P>0.05), however levels of overall activity decreased as broilers aged. Compared with the control, flight distances in unenriched areas were significantly lower in the perches+dust bath treatment (P=0.026), and were numerically lower in the perches treatment. This suggests a reduction in fearfulness with increased environmental complexity, and thus possible welfare benefits. It is suggested that further research should investigate whether increasing the level of provision of these enrichments leads to more marked improvements in welfare.

A multicentre, UK, retrospective, observational study to assess the effectiveness of insulin glargine 300 units/ml in treating people with Type 1 diabetes mellitus in routine clinical practice (SPARTA).

AIM: To conduct an open-label study to provide UK real-world evidence regarding the use of insulin glargine 300 units/ml (U300) in people with Type 1 diabetes mellitus. METHODS: People with Type 1 diabetes who had been prescribed U300 ≥6 months before data collection and had HbA1c levels recorded within 3 months prior to U300 (baseline) were included. The primary endpoint was change in HbA1c from baseline to month 6 after U300 initiation. Other endpoints included number of documented hypoglycaemic and diabetic ketoacidosis episodes, and change in daily basal insulin dose. RESULTS: A total of 298 people with Type 1 diabetes were included [mean age 42.1 years, mean HbA1c 79 mmol/mol (9.4%)]. After U300 initiation, the mean reduction in HbA1c from baseline to month 6 was -4 mmol/mol (-0.4%; P<0.001; n=188). The total daily basal insulin dose at 6 months was 1.3 units higher than at the time of U300 initiation (P<0.001; n=275) but was not significantly different from the prior basal insulin dose. There was no clinically significant difference in weight between baseline and month 6 [mean difference +0.7 kg, 95% CI -0.1, 1.5; P=0.084; n=115). During the 6 months before and after U300 initiation, severe hypoglycaemic episodes were documented for 6/298 and 4/298 participants. Diabetic ketoacidosis episodes requiring Accident and Emergency department visits or hospitalization were documented for 4/298 and 6/298 participants, before and after U300 initiation, respectively. CONCLUSIONS: In people with Type 1 diabetes, a change in basal insulin to U300 was associated with clinically and statistically significant HbA1c improvements, without significant changes in basal insulin dose and weight. Documented severe hypoglycaemia episodes and diabetic ketoacidosis requiring Accident and Emergency department visits or hospitalization were low and similar before and after U300 initiation.

A retrospective observational study of people with Type 1 diabetes with self-reported severe hypoglycaemia reveals high level of ambulance attendance but low levels of therapy change and specialist intervention.

AIM: To evaluate the impact of severe hypoglycaemia on NHS resources and overall glycaemic control in adults with Type 1 diabetes. METHODS: An observational, retrospective study of adults (aged ≥ 18 years) with Type 1 diabetes reporting one or more episodes of severe hypoglycaemia during the preceding 24 months in 10 NHS hospital diabetes centres in England and Wales. The primary outcome was healthcare resource utilization associated with severe hypoglycaemia. Secondary outcomes included demographic and clinical characteristics, diabetes control and pathway of care. RESULTS: Some 140 episodes of severe hypoglycaemia were reported by 85 people during the 2-year observation period. Ambulances were called in 99 of 140 (71%) episodes and Accident and Emergency attendance occurred in 26 of 140 (19%) episodes, whereas 29 of 140 (21%) episode required no immediate help from healthcare providers. Participants attended a median of 5 (range 0-58) diabetes clinic consultations during the observation period; 13% (70 of 552) of all consultations were severe hypoglycaemia-related. Of the HbA1c measurements recorded closest prior to severe hypoglycaemia (n = 119), only 7 of 119 measurements were < 48 mmol/mol (< 6.5%) and mean HbA1c was 70 (sd 19) mmol/mol (8.5%, sd 1.7%). Some 119 changes to diabetes treatment were recorded during the observation period (median/person 0;, range 0-11), of which 52 of 119 changes (44%) followed severe hypoglycaemic events. CONCLUSIONS: We observed a high level of ambulance service intervention but surprisingly low levels of hypoglycaemia follow-up, therapy change and specialist intervention in people self-reporting severe hypoglycaemia. These results suggest there may be important gaps in care pathways for people with Type 1 diabetes self-reporting severe hypoglycaemia.