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Background Immune checkpoint inhibitors (ICI) improve survival but cause immune-related adverse events (irAE). We sought to determine if CTCAE classification, IBD biomarkers/endoscopic/histological scores correlate with irAE colitis outcomes. Methods A dual-centre retrospective study was performed on patients receiving ICI for melanoma, NSCLC or urothelial cancer from 2012 to 2018. Demographics, clinical data, endoscopies (reanalysed using Mayo/Ulcerative Colitis Endoscopic Index of Severity (UCEIS) scores), histology (scored with Nancy Index) and treatment outcomes were analysed. Results In all, 1074 patients were analysed. Twelve percent (134) developed irAE colitis. Median patient age was 66, 59% were male. CTCAE diarrhoea grade does not correlate with steroid/ infliximab use. G3/4 colitis patients are more likely to need infliximab ( p  < 0.0001) but colitis grade does not correlate with steroid duration. CRP, albumin and haemoglobin do not correlate with severity. The UCEIS ( p  = 0.008) and Mayo ( p  = 0.016) scores correlate with severity/infliximab requirement. Patients with higher Nancy indices (3/4) are more likely to require infliximab ( p  = 0.03). Conclusions CTCAE assessment does not accurately reflect colitis severity and our data do not support its use in isolation, as this may negatively impact timely management. Our data support utilising endoscopic scoring for patients with >grade 1 CTCAE disease, and demonstrate the potential prognostic utility of objective histologic scoring.

Barrett’s oesophagus is a precursor of oesophageal adenocarcinoma. In this common condition, squamous epithelium in the oesophagus is replaced by columnar epithelium in response to acid reflux. Barrett’s oesophagus is highly heterogeneous and its relationships to normal tissues are unclear. Here we investigate the cellular complexity of Barrett’s oesophagus and the upper gastrointestinal tract using RNA-sequencing of single cells from multiple biopsies from six patients with Barrett’s oesophagus and two patients without oesophageal pathology. We find that cell populations in Barrett’s oesophagus, marked by LEFTY1 and OLFM4 , exhibit a profound transcriptional overlap with oesophageal submucosal gland cells, but not with gastric or duodenal cells. Additionally, SPINK4 and ITLN1 mark cells that precede morphologically identifiable goblet cells in colon and Barrett’s oesophagus, potentially aiding the identification of metaplasia. Our findings reveal striking transcriptional relationships between normal tissue populations and cells in a premalignant condition, with implications for clinical practice. Barrett’s oesophagus is associated with an increased risk of oseophageal cancer, but its cell of origin is unclear. Here the authors show, using single-cell RNA sequencing of biopsies from six patients and two unaffected subjects, that cells in Barrett’s oesophagus show a transcriptional profile that is similar to that of cells in oesophageal submucosal glands.

There is substantial evidence to indicate that the DNA repair protein O6-alkylguanine-DNA alkyltransferase (ATase) plays a major role in cellular resistance to the cytotoxic effects of O6-alkylating agent chemotherapies, including temozolomide. Depletion of ATase in tumours prior to treatment might therefore be expected to improve clinical outcomes with these drugs. In the first part of this thesis the relationship between melanoma ATase expression and response to temozolomide was examined. No correlation was found, but heterogeneity tumour ATase expression and downstream resistance mechanisms might account for this. Altering the schedule of temozolomide to allow dosing at the ATase nadir following prior administration might enhance the drug's activity. This was explored in an animal model, where 4-hourly administration of temozolomide delayed melanoma xenograft growth significantly more than the standard 24- hourly dosing regimen. Increased tumour DNA methylation, compared with standard therapy, was observed with the compressed schedule, and might be the basis for the increased anti-tumour effect. However, toxicity was also increased making it unclear if an improvement in therapeutic index could be achieved. A clinical trial in melanoma patients established that the response rate with temozolomide was increased, but at the expense of increased haematological toxicity. Tumour and peripheral blood mononuclear cell DNA methylation were increased compared with standard treatment regimens. Pre-treatment peripheral blood mononuclear cell ATase predicted for haematological toxicity, a fmding borne out with other schedules of temozolomide administration. Indirect inactivation of ATase via cytotoxic agents has yielded little clinical benefit, so interest has turned to non-toxic pseudosubstrate inactivators of the protein. One such inactivator, O6-(4-bromothenyl)guanine (4BTG), was tested in combination with temozolomide in a number of animal tumour models. 4BTG enhanced the effect of temozolomide against a range of tumours, with little or no additional toxicity. 4BTG also appeared to attenuate the development of resistance to temozolomide in xenografts. The biodistribution of 4BTG was studied using radiolabelled compound. These studies have established that compressed scheduling of temozolomide, whilst improving response rates, is of limited clinical use due to increased toxicity. Direct ATase inactivation using 4BTG holds more promise, and the combination of 4BTG and temozolomide is now in clinical trials.

Barretts esophagus is a precursor of esophageal adenocarcinoma. In this common condition, squamous epithelium in the esophagus is replaced by columnar epithelium in response to acid reflux. Barretts esophagus is highly heterogeneous and its relationships to normal tissues are unclear. We investigated the cellular complexity of Barretts esophagus and the upper gastrointestinal tract using RNA-sequencing of 2895 single cells from multiple biopsies from four patients with Barretts esophagus and two patients without esophageal pathology. We found that uncharacterised cell populations in Barretts esophagus, marked by LEFTY1 and OLFM4, exhibit a profound transcriptional overlap with a subset of esophageal cells, but not with gastric or duodenal cells. Additionally, SPINK4 and ITLN1 mark cells that precede morphologically identifiable goblet cells in colon and Barretts esophagus, potentially aiding the identification of metaplasia. Our findings reveal striking transcriptional relationships between normal tissue populations and cells in a premalignant condition, with implications for clinical practice.

Thyroid peroxidase antibodies may increase the risk of miscarriage and preterm birth. In this controlled trial, the use of levothyroxine before conception and through birth did not improve live-birth rates among euthyroid women with such antibodies and a history of miscarriage or infertility.

We aimed to assess the efficacy and safety of sequential or simultaneous telomerase vaccination (GV1001) in combination with chemotherapy in patients with locally advanced or metastatic pancreatic cancer. TeloVac was a three-group, open-label, randomised phase 3 trial. We recruited patients from 51 UK hospitals. Eligible patients were treatment naive, aged older than 18 years, with locally advanced or metastatic pancreatic ductal adenocarcinoma, and Eastern Cooperative Oncology Group performance status of 0–2. Patients were randomly assigned (1:1:1) to receive either chemotherapy alone, chemotherapy with sequential GV1001 (sequential chemoimmunotherapy), or chemotherapy with concurrent GV1001 (concurrent chemoimmunotherapy). Treatments were allocated with equal probability by means of computer-generated random permuted blocks of sizes 3 and 6 in equal proportion. Chemotherapy included six cycles of gemcitabine (1000 mg/m2, 30 min intravenous infusion, at days 1, 8, and 15) and capecitabine (830 mg/m2 orally twice daily for 21 days, repeated every 28 days). Sequential chemoimmunotherapy included two cycles of combination chemotherapy, then an intradermal lower abdominal injection of granulocyte-macrophage colony-stimulating factor (GM-CSF; 75 μg) and GV1001 (0·56 mg; days 1, 3, and 5, once on weeks 2–4, and six monthly thereafter). Concurrent chemoimmunotherapy included giving GV1001 from the start of chemotherapy with GM-CSF as an adjuvant. The primary endpoint was overall survival; analysis was by intention to treat. This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN4382138. The first patient was randomly assigned to treatment on March 29, 2007, and the trial was terminated on March 27, 2011. Of 1572 patients screened, 1062 were randomly assigned to treatment (358 patients were allocated to the chemotherapy group, 350 to the sequential chemoimmunotherapy group, and 354 to the concurrent chemoimmunotherapy group). We recorded 772 deaths; the 290 patients still alive were followed up for a median of 6·0 months (IQR 2·4–12·2). Median overall survival was not significantly different in the chemotherapy group than in the sequential chemoimmunotherapy group (7·9 months [95% CI 7·1–8·8] vs 6·9 months [6·4–7·6]; hazard ratio [HR] 1·19, 98·25% CI 0·97–1·48, p=0·05), or in the concurrent chemoimmunotherapy group (8·4 months [95% CI 7·3–9·7], HR 1·05, 98·25% CI 0·85–1·29, p=0·64; overall log-rank of χ22df=4·3; p=0·11). The commonest grade 3–4 toxic effects were neutropenia (68 [19%] patients in the chemotherapy group, 58 [17%] patients in the sequential chemoimmunotherapy group, and 79 [22%] patients in the concurrent chemoimmunotherapy group; fatigue (27 [8%] in the chemotherapy group, 35 [10%] in the sequential chemoimmunotherapy group, and 44 [12%] in the concurrent chemoimmunotherapy group); and pain (34 [9%] patients in the chemotherapy group, 39 [11%] in the sequential chemoimmunotherapy group, and 41 [12%] in the concurrent chemoimmunotherapy group). Adding GV1001 vaccination to chemotherapy did not improve overall survival. New strategies to enhance the immune response effect of telomerase vaccination during chemotherapy are required for clinical efficacy. Cancer Research UK and KAEL-GemVax.

To describe the prevalence of and factors associated with different thyroid dysfunction phenotypes in women who are asymptomatic preconception. Observational cohort study. A total of 49 hospitals across the United Kingdom between 2011 and 2016. Women aged 16 to 41years with history of miscarriage or subfertility trying for a pregnancy. Prevalences and 95% confidence intervals (CIs) were estimated using the binomial exact method. Multivariate logistic regression analyses were conducted to identify risk factors for thyroid disease. None. Rates of thyroid dysfunction. Thyroid function and thyroid peroxidase antibody (TPOAb) data were available for 19213 and 19237 women, respectively. The prevalence of abnormal thyroid function was 4.8% (95% CI, 4.5-5.1); euthyroidism was defined as levels of thyroid-stimulating hormone (TSH) of 0.44 to 4.50 mIU/L and free thyroxine (fT4) of 10 to 21 pmol/L. Overt hypothyroidism (TSH > 4.50 mIU/L, fT4 < 10 pmol/L) was present in 0.2% of women (95% CI, 0.1-0.3) and overt hyperthyroidism (TSH < 0.44 mIU/L, fT4 > 21 pmol/L) was present in 0.3% (95% CI, 0.2-0.3). The prevalence of subclinical hypothyroidism (SCH) using an upper TSH concentration of 4.50 mIU/L was 2.4% (95% CI, 2.1-2.6). Lowering the upper TSH to 2.50 mIU/L resulted in higher rates of SCH, 19.9% (95% CI, 19.3-20.5). Multiple regression analyses showed increased odds of SCH (TSH > 4.50 mIU/L) with body mass index (BMI) ≥ 35.0 kg/m2 (adjusted odds ratio [aOR] 1.71; 95% CI, 1.13-2.57; P = 0.01) and Asian ethnicity (aOR 1.76; 95% CI, 1.31-2.37; P < 0.001), and increased odds of SCH (TSH ≥ 2.50 mIU/L) with subfertility (aOR 1.16; 95% CI, 1.04-1.29; P = 0.008). TPOAb positivity was prevalent in 9.5% of women (95% CI, 9.1-9.9). The prevalence of undiagnosed overt thyroid disease is low. SCH and TPOAb are common, particularly in women with higher BMI or of Asian ethnicity. A TSH cutoff of 2.50 mIU/L to define SCH results in a significant proportion of women potentially requiring levothyroxine treatment.

Background Often people experience ongoing health challenges after stroke. The Australian Stroke Clinical Registry collects patient‐reported outcomes after stroke. Many patients report challenges that are potentially addressable through additional support. Aims To co‐design a registry‐based, hospital‐initiated, follow‐up service for people who report major health‐related challenges between 90 and 180 days after their stroke. Methods Iterative, consensus‐based methods were used to co‐design a follow‐up service intervention including eligibility criteria, clinical protocol (consultation/communication forms and pathways) and implementation requirements (e.g., training manual) (May 2022–March 2023). Stakeholders, including Australian‐based clinicians providing stroke care, researchers and people with lived experience of stroke, were involved in each stage. Data collection: Stage 1 (development), (i) scoping survey; (ii) two consensus meetings; (iii) interviews with key informants (n = 3); (iv) online modified Delphi survey; Stage 2 (testing and finalisation), (v) piloting of the follow‐up service intervention at one hospital, with service coordinator/study team interview and participant satisfaction surveys and; (vi) final review (modified Delphi survey). Consensus was defined in the modified Delphi surveys as ≥ 80% ‘agreement’ or verbal consensus via open voting during meetings. Additional recommendations from each step were iteratively incorporated to refine the intervention. Results Scoping survey results (n = 41/108 respondents, 38% response rate) highlighted the need for broad inclusion criteria and the involvement of carers/support person and general practitioners. During the consensus meetings (16/18, 89% stakeholders attended at least one), verbal consensus was achieved for the eligibility criteria, and additional recommendations were made for the referral report and components within the clinical protocol and training manual. After the final Stage 1 modified Delphi survey (n = 10, two cohorts), 70%–100% consensus was achieved for the referral report, clinical protocol components and training manual, which were then piloted with six eligible participants. Feedback from the pilot testing (n = 3 coordinator/staff interviews; n = 5 satisfaction surveys) led to further clinical protocol modifications. Agreement was reached for all additional recommendations during the final modified Delphi survey round (16/29 respondents, 55%). Conclusion We describe an iterative, consensus‐based co‐design process which resulted in a novel, registry‐based follow‐up service intervention for people living with stroke reporting major health challenges. A feasibility randomised controlled trial is the next stage. Patient or Public Contribution People with lived experience of stroke, including their family/caregivers, actively participated throughout the co‐design process to develop and test the follow‐up service intervention. There was lived experience representation with scoping survey responses, as well as within the working group and independent review group who were involved with the consensus meetings and modified Delphi process. Survey feedback from people with stroke who piloted the developed service intervention was also integral to informing the final service intervention.

IntroductionRotavirus vaccines were introduced into the Australian National Immunisation Program in 2007. Despite this, Northern Territory Indigenous children continue to be hospitalised with rotavirus at a rate more than 20 times higher than non-Indigenous children in other Australian jurisdictions, with evidence of waning protection in the second year of life. We hypothesised that scheduling an additional (third) dose of oral human rotavirus vaccine (Rotarix, GlaxoSmithKline) for children aged 6 to <12 months would improve protection against clinically significant all-cause gastroenteritis.Methods and analysisThis Bayesian adaptive clinical trial will investigate whether routinely scheduling an additional dose of Rotarix for Australian Indigenous children aged 6 to <12 months old confers significantly better protection against clinically important all-cause gastroenteritis than the current two-dose schedule at 2 and 4 months old. There are two coprimary endpoints: (1) seroconversion from baseline serum anti-rotavirus immunoglobulin A (IgA) titre <20 U/mL prior to an additional dose of Rotarix/placebo to serum anti-rotavirus IgA titre >20 U/mL following the administration of the additional dose of Rotarix/placebo and (2) time from randomisation to medical attendance (up to age 36 months old) for which the primary reason is acute gastroenteritis/diarrhoea. Secondary endpoints include the change in anti-rotavirus IgA log titre, time to hospitalisation for all-cause diarrhoea and for rotavirus-confirmed gastroenteritis/diarrhoea, and rotavirus notification. Analysis will be based on Bayesian inference with adaptive sample size.Ethics, registration and disseminationEthics approval has been granted by Central Australian Human Research Ethics Committee (HREC-16-426) and Human Research Ethics Committee of the Northern Territory Department of Health and Menzies School of Health Research (HREC-2016-2658). Study investigators will ensure the trial is conducted in accordance with the principles of the Declaration of Helsinki and with the ICH Guidelines for Good Clinical Practice. Individual participant consent will be obtained. Results will be disseminated via peer-reviewed publication. The trial is registered with Clinicaltrials.gov (NCT02941107) and important modifications to this protocol will be updated.Trial registration numberNCT02941107; Pre-results.

Background Stroke affects long-term physical and cognitive function; many survivors report unmet health needs, such as pain or depression. A hospital-led follow-up service designed to address ongoing health problems may avoid unplanned readmissions and improve quality of life. Methods This paper outlines the protocol for a registry-based, randomised controlled trial with allocation concealment of participants and outcome assessors. Based on an intention-to-treat analysis, we will evaluate the feasibility, acceptability, potential effectiveness and cost implications of a new tailored, codesigned, hospital-led follow-up service for people within 6–12 months of stroke. Participants ( n  = 100) from the Australian Stroke Clinical Registry who report extreme health problems on the EuroQol EQ-5D-3L survey between 90 and 180 days after stroke will be randomly assigned (1:1) to intervention (follow-up service) or control (usual care) groups. All participants will be independently assessed at baseline and 12–14-week post-randomisation. Primary outcomes for feasibility are the proportion of participants completing the trial and for intervention participants the proportion that received follow-up services. Acceptability is satisfaction of clinicians and participants involved in the intervention. Secondary outcomes include effectiveness: change in extreme health problems (EQ-5D-3L), unmet needs (Longer-term Unmet Needs questionnaire), unplanned presentations and hospital readmission, functional independence (modified Rankin Scale) and cost implications estimated from self-reported health service utilisation and productivity (e.g. workforce participation). To inform future research or implementation, the design contains a process evaluation including clinical protocol fidelity and an economic evaluation. Discussion The results of this study will provide improved knowledge of service design and implementation barriers and facilitators and associated costs and resource implications to inform a future fully powered effectiveness trial of the intervention. Trial registration ACTRN12622001015730pr. Trial sponsor Florey Institute of Neuroscience and Mental Health, 245 Burgundy Street, Heidelberg, VIC, 3084, PH: +61 3 9035 7032