U-PRO-CRM: designing patient-centred dose-finding trials with patient-reported outcomes.

BACKGROUND: Determining the maximum tolerated dose (MTD) remains the primary objective for the majority of dose-finding oncology trials. Whilst MTD determination often relies upon clinicians to identify dose-limiting toxicities (DLTs) experienced by patients during the trial, research suggests that clinicians may underreport patient's adverse events. Therefore, contemporary practice may be exposed to recommending intolerable doses to patients for further investigation in subsequent trials. There is increasing interest in patients self-assessing their own symptoms using patient-reported outcomes (PROs) in dose-finding trials. DESIGN: We present Utility-PRO-Continual Reassessment Method (U-PRO-CRM), a novel trial design which simultaneously uses clinician-rated and patient-rated DLTs (Clinician-DLTs and Patient-DLTs, respectively) to make dose (de-)escalation decisions and to recommend an MTD. U-PRO-CRM contains the published PRO-CRM as a special case and provides greater flexibility to trade-off the rate of Patient-DLTs and Clinician-DLTs to find an optimal dose. We present simulation results for U-PRO-CRM. RESULTS: For specified trade-offs between Clinician-DLT and Patient-DLT rate, U-PRO-CRM outperforms the PRO-CRM design by identifying the true MTD more often. In the special case where U-PRO-CRM generalises to PRO-CRM, U-PRO-CRM performs as well as its published counterpart. U-PRO-CRM minimises the number of patients overdosed whilst maintaining a similar proportion of patients allocated to the true MTD. CONCLUSIONS: By using a utility-based dose selection approach, U-PRO-CRM offers the flexibility to define a trade-off between the risk of patient-rated and clinician-rated DLTs for an optimal dose. Patient-centric dose-finding strategies, which integrate PROs, are poised to assume an ever more pivotal role in significantly advancing our understanding of treatment tolerability. This bears significant implications in shaping the future landscape of early-phase trials.

The Utility of Sirolimus Eluting Balloons in the Setting of Chronic Limb Threatening Ischaemia in Asian Patients from Singapore - 12 Months Results of the PRISTINE Registry.

PURPOSE: The aim of PRISTINE was to evaluate the 6 and 12 months safety and efficacy of the Selution Sustained Limus Release (SLR)™ sirolimus-coated balloon for treatment of complex lower limb occlusive lesions (TASC II C & D) in patients with chronic limb threatening ischemia (CLTI) from Singapore. METHODS: PRISTINE was a prospective, non-randomized, single arm, observational, multi-investigator, single-center clinical study. Complication-free survival at 30 days was the safety clinical endpoint. Immediate technical success (ability to cross and dilate the lesion and achieve residual angiographic stenosis < 30%), 6-month primary vessel patency, limb salvage, clinically driven target lesion revascularization (TLR) and amputation free survival (AFS) were the efficacy endpoints of interest. RESULTS: Seventy five patients were included. There were 50 (68.0%) males; mean age, 69.0 ± 10.7 years. CLTI severity was based on the Rutherford Scale (R5 = 51; R6 = 17). Significant co-morbidities included diabetes mellitus (n = 68; 91.0%) and end-stage renal failure (n = 28; 37.0%). 112 atherosclerotic lesions were treated (TASC II D = 58 (52%); 76 (67%) de novo). There was 100% technical success. Mean lesion length treated was 22.4 ± 13.9 cm. Primary vessel patencies at 6 and 12 months were 64/86 (74%) and 43/74 (58%) and freedom from clinically driven TLR were 72/86 (84%) and 55/74 (74%) respectively. AFS was 61/73 (84.0%; five deaths and seven major lower extremity amputation) at 6-months. Mean Rutherford score improved from 5.1 ± 0.55 at baseline to 1.1 ± 2.05 (p < 0.05) at one year and there was a wound healing rate of 38/48 (79%) at the same timepoint. CONCLUSIONS: The Selution SLR™ drug eluting balloon is safe and efficacious in treating highly complex infra-inguinal atherosclerotic lesions in an otherwise challenging frail population of CLTI patients with a high incidence of diabetes and end-stage renal failure. It is associated with highly satisfactory acute technical and clinical success, 12-month target lesion patency and AFS. LEVEL OF EVIDENCE: Level 2b, Individual Cohort Study.

Accrual and statistical power failure in published adjuvant phase III oncology trials: a comprehensive analysis from 2013 to 2023.

BACKGROUND: In a competitive landscape with many ongoing adjuvant randomised controlled trials (RCTs), the prevalence of trials that failed to recruit their targeted sample size and were inadequately powered is unclear. The aims of the study are (i) to determine the percentage of trials with accrual and statistical power failure and (ii) to evaluate their potential impact on the drug development process. MATERIALS AND METHODS: A systematic review was carried out to identify adjuvant phase III oncology RCTs reported between 2013 and 2023 across all solid tumours. No restrictions were applied regarding the type of intervention or journal of publication. The percentage of trials with accrual failure and power failure was estimated as well as their association with the efficacy endpoints. Logistic regression models were used to estimate the odds ratio (OR) and its 95% confidence interval (CI). RESULTS: A total of 282 RCTs met the inclusion criteria with a median sample size of 661 patients and a median accrual period of 4.3 years. Most of these studies were superiority trials (83.0%). Accrual failure was observed in 22.0% of the studies, finishing recruitment without achieving the targeted sample size. Overall, 39.7% of the studies experienced power failure, having less power than specified in the protocol at the date of the read-out. Among superiority RCTs evaluating intermediate survival endpoints, only 31.1% presented statistically significant results. Trials with power failure were less likely to present statistically significant results (37.9% versus 21.9%, P = 0.04). The association was consistent across all cancer types. In the subset of non-inferiority trials, 35.0% formally demonstrated non-inferiority of the experimental arm. CONCLUSIONS: Nearly 40% of adjuvant phase III RCTs experienced power failure, and the reduction in power significantly impacted the final study results. There is a need for procedural refinements in the design and implementation of future adjuvant RCTs to mitigate these fallacies.

Collapse of late endosomal pH elicits a rapid Rab7 response via V-ATPase and RILP.

Endosomal-lysosomal trafficking is accompanied by the acidification of endosomal compartments by the H+-V-ATPase to reach low lysosomal pH. Disruption of proper pH impairs lysosomal function and the balance of protein synthesis and degradation (proteostasis). We used the small dipeptide LLOMe, which is known to permeabilize lysosomal membranes, and find that LLOMe also impacts late endosomes (LEs) by neutralizing their pH without causing membrane permeabilization. We show that LLOMe leads to hyper-activation of Rab7 and disruption of tubulation and mannose-6-phosphate receptor (CI-M6PR) recycling on pH-neutralized LEs. Either pH neutralization (NH4Cl) or Rab7 hyper-active mutants alone can phenocopy the alterations in tubulation and CI-M6PR trafficking. Mechanistically, pH neutralization increases the assembly of the V1G1 subunit of the V-ATPase on endosomal membranes, which stabilizes GTP-bound Rab7 via RILP, a known interactor of Rab7 and V1G1. We propose a novel pathway by which V-ATPase and RILP modulate LE pH and Rab7 activation in concert. This pathway might broadly contribute to pH control during physiologic endosomal maturation or starvation and during pathologic pH neutralization, which occurs via lysosomotropic compounds or in disease states.

The different shapes of the fourth ventricle.

With a distinctive shape and surrounding anatomical structures, the fourth ventricle is located in the posterior cranial fossa. There are various pathologies, either developmental or acquired, that can present as a characteristic deformity of the fourth ventricle. Therefore, this paper will cover the anatomy of the fourth ventricle and correlate this to the various pathologies. The aim of this review is to improve the ability of the readers to recognise the change in shape and configuration of the fourth ventricle, enabling early detection of pathologies.

Exploring the expression and potential function of follicle stimulating hormone receptor in extragonadal cells related to abdominal aortic aneurysm.

INTRODUCTION: Follicle stimulating hormone (FSH) is identified to play a role in postmenopausal disease and hypothesized to affect abdominal aortic aneurysm (AAA) onset/progression in postmenopausal women. We aimed to detect FSHR gene expression in AAA tissue and cell types involved in AAA formation. METHODS: FSH stimulation of human umbilical cord endothelial cells (HUVECs), smooth muscle cells (HUCs) and PMA-differentiated macrophages to assess gene expression of FSHR and various markers. Human macrophages activated with various stimuli were assessed for FSHR gene expression. AAA dataset, AAA tissue samples and AAA-derived smooth muscle cells (SMC) obtained from elderly female donors were assessed for FSHR gene expression. AAA-SMCs were stimulated with FSH to assess its effect on gene expression. Lastly, oxidized low-density-lipoprotein (ox-LDL) uptake and abundance of cell surface protein markers were assessed by flow cytometry after FSH stimulation of human monocytes. RESULTS: FSH stimulation showed similar levels of gene expression in HUVECs and HUCs. Only ACTA2 was downregulated in HUCs. In PMA-differentiated macrophages, gene expression of inflammation markers was unchanged after FSH stimulation. FSHR gene expression was found to be low in the AAA datasets. Female AAA-SMCs show occasional FSHR gene expression at a very low level, yet stimulation with FSH did not affect gene expression of SMC- or inflammation markers. FSH stimulation did not impact ox-LDL uptake or alter cell surface protein expression in monocytes. While FSHR gene expression was detected in human testis tissue, it was below quantification level in all other investigated cell types, even upon activation of macrophages with various stimuli. CONCLUSION: Despite previous reports, we did not detect FSHR gene expression in various extragonadal cell types, except in occasional female AAA-SMCs. No clear effect on cell activation was observed upon FSH stimulation in any cell type. Our data suggest that a direct effect of FSH in AAA-related extragonadal cells is unlikely to influence AAA.

Effects of antifouling compounds on the growth of macroalgae Undaria pinnatifida.

Seaweeds are some of the principal primary producers of marine environments, and they are important ecological elements of coastal ecosystems. The effects of harmful chemicals on seaweeds may adversely affect coastal ecosystems, hence we aimed to develop a new phytotoxicity test using the gametophytes of a common temperate kelp species, Undaria pinnatifida (KU-1630), for the widely used antifouling chemical substances Cybutryne, Diuron, Cu2+, and Zn2+. Toxicity to gametophytes of U. pinnatifida was assessed by comparing the relative growth rate (RGR) at the logarithmic growth phase. Fragmentation method, initial algal biomass, photon irradiance, and adhesive period were investigated for developing optimal test conditions. Cybutryne exposure tests were performed with seven replicates and control, the RGR ranging from 0.17 to 0.19, while mean 7-day EC50 and no observed effect concentration (NOEC) were 5.1 µg/L and 1.8 µg/L, respectively. The 7-day EC50 for other antifoulants was 14 µg/L for Diuron, 17 µg/L for Cu2+, and 1500 µg/L for Zn2+. This test method demonstrated high sensitivity and reproducibility, and it may be added to the routine methods used for toxicity evaluation of hazardous chemicals.

Oncology phase I trial design and conduct: time for a change - MDICT Guidelines 2022.

In 2021, the Food and Drug Administration Oncology Center of Excellence announced Project Optimus focusing on dose optimization for oncology drugs. The Methodology for the Development of Innovative Cancer Therapies (MDICT) Taskforce met to review and discuss the optimization of dosage for oncology trials and to develop a practical guide for oncology phase I trials. Defining a single recommended phase II dose based on toxicity may define doses that are neither the most effective nor the best tolerated. MDICT recommendations address the need for robust non-clinical data which are needed to inform trial design, as well as an expert team including statisticians and pharmacologists. The protocol must be flexible and adaptive, with clear definition of all endpoints. Health authorities should be consulted early and regularly. Strategies such as randomization, intrapatient dose escalation, and real-world eligibility criteria are encouraged whereas serial tumor sampling is discouraged in the absence of a strong rationale and appropriately validated assay. Endpoints should include consideration of all longitudinal toxicity. The phase I dose escalation trial should define the recommended dose range for later testing in randomized phase II trials, rather than a single recommended phase II dose, and consider scenarios where different populations may require different dosages. The adoption of these recommendations will improve dosage selection in early clinical trials of new anticancer treatments and ultimately, outcomes for patients.

Accessory Vein Obliteration and Balloon-Assisted Maturation for Immature Arteriovenous Fistulas for Haemodialysis: A Systematic Review and Meta-Analysis.

PURPOSE: This study aims to examine outcomes of immature arteriovenous fistula salvage using balloon angioplasty (PTA) without and with accessory vein obliteration (PTA + VO). MATERIALS AND METHODS: PubMed and Embase were accessed on 21 September 2020 to retrieve cohort studies on adult patients with end-stage renal failure (ESRF) requiring dialysis. Risk of bias was assessed using Newcastle-Ottawa Scale. Studies were pooled into PTA or PTA + VO arms, with outcomes (technical/clinical success, primary/secondary post-intervention patency until 12 months) reported as event rates with 95% confidence intervals. Random-effects model and maximum likelihood meta-regression were used for meta-analysis. RESULTS: Fourteen studies (1030 participants) were included. The between-subgroup difference in outcomes was largely non-significant (p > 0.050). CONCLUSION: The evidence does not support balloon angioplasty with concomitant accessory vein obliteration for immature fistula salvage.

Utility of sirolimus coated balloons in the peripheral vasculature - a review of the current literature.

Sirolimus-coated balloons (SCB) have demonstrated much promise as an alternative drug eluting device to the existing paclitaxel coated balloon platforms for the treatment of peripheral arterial disease (PAD). They have been well tested pre-clinically and have demonstrated anti-restenotic effects as well as clinical safety in its use for treatment of coronary artery disease. The existing approved SCBs have thus far demonstrated good short-term patency (12-months) and did not exhibit any major adverse events or device related shortcomings in its use for treatment of PAD. There are several studies ongoing which aim to further investigate the efficacy of existing SCBs and establish a direct comparison of its outcomes compared with plain balloon angioplasty. Also, SCB utility to salvage failing arteriovenous fistulas for haemodialysis patients has also been explored. We review the current progress made in the establishment of SCB in the treatment of PAD as well as highlight ongoing studies investigating the role of SCB in various settings.

Environmental enrichment preserves hippocampal neurons in diabetes and stressed rats.

This study evaluated the effect of Environmental Enrichment (EE) on neuron morphology in the CA1, CA3 and dentate hilus (DH) regions of the hippocampus by quantitating the total dendritic arborizations. EE is a potential intervention for stress and diabetes. It is capable of mitigating diabetes and stress-induced cognitive and memory deficit. Diabetes and stress were induced in male Wistar rats (4-5 weeks). Diabetic and stressed rats were exposed to EE on Day 2 post STZ injection and subsequently once daily for 30 days. All animals were sacrificed on Day 30. The hippocampus was dissected and processed for Golgi staining to quantitate dendritic arborizations at the CA1, CA2 and DH regions. Diabetes (D) and Diabetes+stress (D+S) groups had significantly fewer apical and basal dendritic branching points (ADBP, BDBP) at CA1 (p<0.01), CA3 (p<0.001) and DH (p<0.001) relative to control group (NC). Diabetes and stressed rats exposed to EE: [D+EE and D+S+EE groups] exhibited significantly denser ADBP and BDBP at all regions relative to D (p<0.001) and (D+S+EE) (p<0.001) groups respectively. EE significantly preserved neuronal arborizations in hippocampus of diabetic and stressed rats, suggesting a potential entity of diabetes and stress management.

An Observational Clinical Trial Examining the Effect of Topical Oxygen Therapy (Natrox™) on the Rates of Healing of Chronic DiAbetic Foot Ulcers (OTONAL Trial).

Natrox™ topical oxygen therapy (TOT) (Inotec AMD Ltd, Cambridgeshire, UK) employs a small battery-powered "oxygen generator" to concentrate atmospheric oxygen and feeds pure, moist, oxygen through a fine, soft tube to a dressing-like "oxygen distribution system", which is placed over the wound and is held in place by a conventional dressing. The aim was to determine the effectiveness of Natrox™ for non-healing diabetic foot ulcers (DFU) over a 3-month period.Longitudinal, single-arm, open prospective registry study using 12 weeks of TOT using a 4 week run-in period. 20 patients recruited to OTONAL had chronic DFU greater than 3 months duration or minor amputation sites with less than 50% healing in 4 weeks.There were 13 (65%) males and the mean age was 65.7 (±11.6) years. The mean glycated haemoglobin (HbA1c) was 6.9 (±1.3) mmol mol-1 and mean wound duration before TOT was 114 (±79.1) days. 18/20 (90.0%) patients had concomitant lower limb revascularization angioplasty for chronic limb threatening ischaemia. The mean size of the foot ulcer at baseline was 11.3 ± 14.8 cm2 and mean transcutaneous oxygen measurement value was 34.1 (±19.6) mm Hg. Wound closure of >75% was observed in 14/20 (70.0%) patients. There was a 91.3% (±14.9%) wound area reduction by 3 months (P = .001) and mean time for 100% closure was 77.6 ± 32.5 days. Mean pain scores reduced from 2.4 (±1.8) at baseline to .5 (±1.0) at 3 months (P = .008). All patients were very satisfied using the ambulatory device. Use of TOT in chronic diabetic foot wounds stimulates a healing state, underpinning the concept that oxygen plays a central role in wound healing. Our results are more compelling if you consider they started with relatively large-sized DFUs and majority of patients were frail with underlying peripheral artery disease. (NCT03863054).

TRAFIC: statistical design and analysis plan for a pragmatic early phase 1/2 Bayesian adaptive dose escalation trial in rheumatoid arthritis.

BACKGROUND: Adaptive model-based dose-finding designs have demonstrated advantages over traditional rule-based designs but have increased statistical complexity but uptake has been slow especially outside of cancer trials. TRAFIC is a multi-centre, early phase trial in rheumatoid arthritis incorporating a model-based design. METHODS: A Bayesian adaptive dose-finding phase I trial rolling into a single-arm, single-stage phase II trial. Model parameters for phase I were chosen via Monte Carlo simulation evaluating objective performance measures under clinically relevant scenarios and incorporated stopping rules for early termination. Potential designs were further calibrated utilising dose transition pathways. DISCUSSION: TRAFIC is an MRC-funded trial of a re-purposed treatment demonstrating that it is possible to design, fund and implement a model-based phase I trial in a non-cancer population within conventional research funding tracks and regulatory constraints. The phase I design allows borrowing of information from previous trials, all accumulated data to be utilised in decision-making, verification of operating characteristics through simulation, improved understanding for management and oversight teams through dose transition pathways. The rolling phase II design brings efficiencies in trial conduct including site and monitoring activities and cost. TRAFIC is the first funded model-based dose-finding trial in inflammatory disease demonstrating that small phase I/II trials can have an underlying statistical basis for decision-making and interpretation. TRIAL REGISTRATION: Trials Registration: ISRCTN, ISRCTN36667085 . Registered on September 26, 2014.

Measuring the quality of cancer care in the Barwon South Western region, Victoria, Australia.

OBJECTIVE: The implementation of clinical quality indicators for monitoring cancer care in regional, rural and remote areas. DESIGN: Retrospective data from a population-based Clinical Quality Registry for lung, colorectal and breast cancers. SETTING: All major health services in the Barwon South Western region, Victoria, Australia. PARTICIPANTS: All patients who were diagnosed with cancer and who presented to a health service. INTERVENTION(S): Clinical subgroups to review variations. MAIN OUTCOME MEASURES(S): Clinical quality indicators for lung, colorectal and breast cancers. RESULTS: Clinical indicators included the following: discussion at multidisciplinary meetings, the timeliness of care provided and the type of care for different stages of the disease and survival outcomes. Many of the derived clinical indicator targets were reached. However, variations led to an improvement in the tumour stage being recorded in the medical record; an improved awareness of the need for adjuvant chemotherapy for colorectal cancer; a reduction in time to treatment for lung cancer and a reduced time to surgery for breast cancer, and the 30-day mortality post-treatment for all of the tumour streams was highlighted. CONCLUSIONS: Clinical quality indicators allow for valuable insights into patterns of care. These indicators are easily reproduced and may be of use to other cancer centres and health services.

Not all swellings are lymph nodes! A case of subcutaneous panniculitis-like T-cell lymphoma.

Subcutaneous Panniculitis-like T-cell Lymphoma (SPTL) is a rare cutaneous neoplasm of mature cytotoxic T cells, first described in 1991 by Gonzalez et al. The incidence of SPTL in Asian countries ranges from 2.3% to 3%. In Malaysia, only 5 cases were reported from 2001 to 2004 in Hospital Kuala Lumpur, Malaysia. SPTL typically presents as skincoloured or erythematous subcutaneous nodules, most often on the extremities and trunk, but it can also involve the face, back and neck. Diagnosis of SPTL is made based on correlation of clinical findings and subcutaneous tissue biopsy along with immunohistochemical staining patterns.

Nestin in immature embryonic neurons affects axon growth cone morphology and Semaphorin3a sensitivity.

Correct wiring in the neocortex requires that responses to an individual guidance cue vary among neurons in the same location, and within the same neuron over time. Nestin is an atypical intermediate filament expressed strongly in neural progenitors and is thus used widely as a progenitor marker. Here we show a subpopulation of embryonic cortical neurons that transiently express nestin in their axons. Nestin expression is thus not restricted to neural progenitors, but persists for 2-3 d at lower levels in newborn neurons. We found that nestin-expressing neurons have smaller growth cones, suggesting that nestin affects cytoskeletal dynamics. Nestin, unlike other intermediate filament subtypes, regulates cdk5 kinase by binding the cdk5 activator p35. Cdk5 activity is induced by the repulsive guidance cue Semaphorin3a (Sema3a), leading to axonal growth cone collapse in vitro. Therefore, we tested whether nestin-expressing neurons showed altered responses to Sema3a. We find that nestin-expressing newborn neurons are more sensitive to Sema3a in a roscovitine-sensitive manner, whereas nestin knockdown results in lowered sensitivity to Sema3a. We propose that nestin functions in immature neurons to modulate cdk5 downstream of the Sema3a response. Thus, the transient expression of nestin could allow temporal and/or spatial modulation of a neuron's response to Sema3a, particularly during early axon guidance.

Author Correction: SMARCA2-regulated host cell factors are required for MxA restriction of influenza A viruses.

A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper.

SMARCA2-regulated host cell factors are required for MxA restriction of influenza A viruses.

The human interferon (IFN)-induced MxA protein is a key antiviral host restriction factor exhibiting broad antiviral activity against many RNA viruses, including highly pathogenic avian influenza A viruses (IAV) of the H5N1 and H7N7 subtype. To date the mechanism for how MxA exerts its antiviral activity is unclear, however, additional cellular factors are believed to be essential for this activity. To identify MxA cofactors we performed a genome-wide siRNA-based screen in human airway epithelial cells (A549) constitutively expressing MxA using an H5N1 reporter virus. These data were complemented with a proteomic screen to identify MxA-interacting proteins. The combined data identified SMARCA2, the ATPase subunit of the BAF chromatin remodeling complex, as a crucial factor required for the antiviral activity of MxA against IAV. Intriguingly, our data demonstrate that although SMARCA2 is essential for expression of some IFN-stimulated genes (ISGs), and the establishment of an antiviral state, it is not required for expression of MxA, suggesting an indirect effect on MxA activity. Transcriptome analysis of SMARCA2-depleted A549-MxA cells identified a small set of SMARCA2-regulated factors required for activity of MxA, in particular IFITM2 and IGFBP3. These findings reveal that several virus-inducible factors work in concert to enable MxA restriction of IAV.

Examining the sources of occupational stress in an emergency department.

BACKGROUND: Previous work has established that health care staff, in particular emergency department (ED) personnel, experience significant occupational stress but the underlying stressors have not been well quantified. Such data inform interventions that can reduce cases of occupational mental illness, burnout, staff turnover and early retirement associated with cumulative stress. AIMS: To develop, implement and evaluate a questionnaire examining the origins of occupational stress in the ED. METHODS: A questionnaire co-designed by an occupational health practitioner and ED management administered to nursing, medical and support staff in the ED of a large English teaching hospital in 2015. The questionnaire assessed participants' demographic characteristics and perceptions of stress across three dimensions (demand-control-support, effort-reward and organizational justice). Work-related stressors in ED staff were compared with those of an unmatched control group from the acute ear, nose and throat (ENT) and neurology directorate. RESULTS: A total of 104 (59%) ED staff returned questionnaires compared to 72 staff (67%) from the acute ENT/neurology directorate. The ED respondents indicated lower levels of job autonomy, management support and involvement in organizational change, but not work demand. High levels of effort-reward imbalance and organizational injustice were reported by both groups. CONCLUSIONS: Our findings suggest that internal ED interventions to improve workers' job control, increase support from management and involvement in organizational change may reduce work stress. The high levels of effort-reward imbalance and organizational injustice reported by both groups may indicate that wider interventions beyond the ED are also needed to address these issues.