Differential Cognitive Effects of Unilateral Subthalamic Nucleus Deep Brain Stimulation for Parkinson's Disease.

OBJECTIVE: The aim of this study was to investigate the cognitive effects of unilateral directional versus ring subthalamic nucleus deep brain stimulation (STN DBS) in patients with advanced Parkinson's disease. METHODS: We examined 31 participants who underwent unilateral STN DBS (left n = 17; right n = 14) as part of an National Institutes of Health (NIH)-sponsored randomized, double-blind, crossover study contrasting directional versus ring stimulation. All participants received unilateral DBS implants in the hemisphere more severely affected by motor parkinsonism. Measures of cognition included verbal fluency, auditory-verbal memory, and response inhibition. We used mixed linear models to contrast the effects of directional versus ring stimulation and implant hemisphere on longitudinal cognitive function. RESULTS: Crossover analyses showed no evidence for group-level changes in cognitive performance related to directional versus ring stimulation. Implant hemisphere, however, impacted cognition in several ways. Left STN participants had lower baseline verbal fluency than patients with right implants (t [20.66 = -2.50, p = 0.02]). Verbal fluency declined after left (p = 0.013) but increased after right STN DBS (p < 0.001), and response inhibition was faster following right STN DBS (p = 0.031). Regardless of hemisphere, delayed recall declined modestly over time versus baseline (p = 0.001), and immediate recall was unchanged. INTERPRETATION: Directional versus ring STN DBS did not differentially affect cognition. Similar to prior bilateral DBS studies, unilateral left stimulation worsened verbal fluency performance. In contrast, unilateral right STN surgery increased performance on verbal fluency and response inhibition tasks. Our findings raise the hypothesis that unilateral right STN DBS in selected patients with predominant right brain motor parkinsonism could mitigate declines in verbal fluency associated with the bilateral intervention. ANN NEUROL 2024;95:1205-1219.

Assessment of endpoint definitions in recurrent and metastatic mucosal head and neck squamous cell carcinoma trials: Head and Neck Cancer International Group consensus recommendations.

Transparent and precise endpoint definitions are a crucial aspect of clinical trial conduct and reporting, and are used to communicate the benefit of an intervention. Previous studies have identified inconsistencies in endpoint definitions across oncological clinical trials. Here, the Head and Neck Cancer International Group assessed endpoint definitions from phase 3 trials or trials considered practice-changing for patients with recurrent or metastatic mucosal head and neck squamous cell carcinoma, published between 2008 and 2021. We identify considerable and global heterogeneity in endpoint definitions, which undermines the interpretation of results and development of future studies. We show how fundamental components of even incontrovertible endpoints such as overall survival vary widely, highlighting an urgent need for increased rigour in reporting and harmonisation of endpoints.

Assessment of endpoint definitions in curative-intent trials for mucosal head and neck squamous cell carcinomas: Head and Neck Cancer International Group consensus recommendations.

Robust time-to-event endpoint definitions are crucial for the assessment of treatment effect and the clinical value of trial interventions. Here, the Head and Neck Cancer International Group investigated endpoint use in phase 3 trials and trials considered potentially practice-changing published between 2008 and 2021 in the curative-intent setting for patients with mucosal head and neck squamous cell carcinoma. Of the 92 trials reviewed, we show that all core components of endpoint reporting were heterogeneous, including definitions of common terms, such as overall survival and progression-free survival. Our report highlights the urgent need for harmonisation of fundamental components of clinical trial endpoints and the engagement of all stakeholders to ensure the transparent reporting of endpoint details.

Implementing effective community-based surveillance in research studies of maternal, newborn and infant outcomes in low resource settings.

BACKGROUND: Globally adopted health and development milestones have not only encouraged improvements in the health and wellbeing of women and infants worldwide, but also a better understanding of the epidemiology of key outcomes and the development of effective interventions in these vulnerable groups. Monitoring of maternal and child health outcomes for milestone tracking requires the collection of good quality data over the long term, which can be particularly challenging in poorly-resourced settings. Despite the wealth of general advice on conducting field trials, there is a lack of specific guidance on designing and implementing studies on mothers and infants. Additional considerations are required when establishing surveillance systems to capture real-time information at scale on pregnancies, pregnancy outcomes, and maternal and infant health outcomes. MAIN BODY: Based on two decades of collaborative research experience between the Kintampo Health Research Centre in Ghana and the London School of Hygiene and Tropical Medicine, we propose a checklist of key items to consider when designing and implementing systems for pregnancy surveillance and the identification and classification of maternal and infant outcomes in research studies. These are summarised under four key headings: understanding your population; planning data collection cycles; enhancing routine surveillance with additional data collection methods; and designing data collection and management systems that are adaptable in real-time. CONCLUSION: High-quality population-based research studies in low resource communities are essential to ensure continued improvement in health metrics and a reduction in inequalities in maternal and infant outcomes. We hope that the lessons learnt described in this paper will help researchers when planning and implementing their studies.

Prospective patient stratification into robust cancer-cell intrinsic subtypes from colorectal cancer biopsies.

Colorectal cancer (CRC) biopsies underpin accurate diagnosis, but are also relevant for patient stratification in molecularly-guided clinical trials. The consensus molecular subtypes (CMSs) and colorectal cancer intrinsic subtypes (CRISs) transcriptional signatures have potential clinical utility for improving prognostic/predictive patient assignment. However, their ability to provide robust classification, particularly in pretreatment biopsies from multiple regions or at different time points, remains untested. In this study, we undertook a comprehensive assessment of the robustness of CRC transcriptional signatures, including CRIS and CMS, using a range of tumour sampling methodologies currently employed in clinical and translational research. These include analyses using (i) laser-capture microdissected CRC tissue, (ii) eight publically available rectal cancer biopsy data sets (n = 543), (iii) serial biopsies (from AXEBeam trial, NCT00828672; n = 10), (iv) multi-regional biopsies from colon tumours (n = 29 biopsies, n = 7 tumours), and (v) pretreatment biopsies from the phase II rectal cancer trial COPERNCIUS (NCT01263171; n = 44). Compared to previous results obtained using CRC resection material, we demonstrate that CMS classification in biopsy tissue is significantly less capable of reliably classifying patient subtype (43% unknown in biopsy versus 13% unknown in resections, p = 0.0001). In contrast, there was no significant difference in classification rate between biopsies and resections when using the CRIS classifier. Additionally, we demonstrated that CRIS provides significantly better spatially- and temporally- robust classification of molecular subtypes in CRC primary tumour tissue compared to CMS (p = 0.003 and p = 0.02, respectively). These findings have potential to inform ongoing biopsy-based patient stratification in CRC, enabling robust and stable assignment of patients into clinically-informative arms of prospective multi-arm, multi-stage clinical trials. © 2018 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

A prospective phase II study of pre-operative chemotherapy then short-course radiotherapy for high risk rectal cancer: COPERNICUS.

BACKGROUND: Neoadjuvant chemotherapy (NAC) allows earlier treatment of rectal cancer micro-metastases but is not standard of care. There are currently no biomarkers predicting long-term progression-free survival (PFS) benefit from NAC. PATIENTS AND METHODS: In this single arm phase II trial, patients with non-metastatic magnetic resonance imaging (MRI)-defined operable rectal adenocarcinoma at high risk of post-operative metastatic recurrence, received 8 weeks of oxaliplatin/fluorouracil NAC then short-course preoperative radiotherapy (SCPRT) before immediate surgery. Sixteen weeks of post-operative adjuvant chemotherapy (AC) was planned. A pelvic MRI was performed at week 9 immediately post-NAC, before SCPRT. The primary end point was feasibility assessed by completion of protocol treatment up to and including surgery. Secondary endpoints included compliance, toxicity, downstaging efficacy, and PFS. RESULTS: In total 60 patients were recruited May 2012-June 2014. In total 57 patients completed protocol treatment, meeting the primary endpoint. Compliance with NAC was much better than AC: Comparing NAC vs. AC, the median percentage dose intensity for fluoropyrimidine was 100% vs. 63% and for oxaliplatin 100% vs. 45%. Treatment-related toxicity was acceptable with no treatment-related deaths. Post-NAC MRI showed 44 tumours (73%) were T-downstaged and 22 (37%) had excellent MRI tumour regression grade (mrTRG 1-2). Median follow-up was 27 months with 2-year PFS of 86.2% (10 events). On exploratory analysis, post-NAC mrTRG predicted PFS with no event among those with excellent regression. CONCLUSION: The regimen was well tolerated with effective downstaging and encouraging PFS. mrTRG response to NAC may be a new prognostic factor for long-term PFS, but needs validation in larger studies.

Immediate chest X-ray for patients at risk of lung cancer presenting in primary care: randomised controlled feasibility trial.

BACKGROUND: Achieving earlier stage diagnosis is one option for improving lung cancer outcomes in the United Kingdom. Patients with lung cancer typically present with symptoms to general practitioners several times before referral or investigation. METHODS: We undertook a mixed methods feasibility individually randomised controlled trial (the ELCID trial) to assess the feasibility and inform the design of a definitive, fully powered, UK-wide, Phase III trial of lowering the threshold for urgent investigation of suspected lung cancer. Patients over 60, with a smoking history, presenting with new chest symptoms to primary care, were eligible to be randomised to intervention (urgent chest X-ray) or usual care. RESULTS: The trial design and materials were acceptable to GPs and patients. We randomised 255 patients from 22 practices, although the proportion of eligible patients who participated was lower than expected. Survey responses (89%), and the fidelity of the intervention (82% patients X-rayed within 3 weeks) were good. There was slightly higher anxiety and depression in the control arm in participants aged >75. Three patients (1.2%) were diagnosed with lung cancer. CONCLUSIONS: We have demonstrated the feasibility of individually randomising patients at higher risk of lung cancer, to a trial offering urgent investigation or usual care.

Effect of early neonatal vitamin A supplementation on mortality during infancy in Ghana (Neovita): a randomised, double-blind, placebo-controlled trial.

BACKGROUND: Results of randomised controlled trials of newborn (age 1-3 days) vitamin A supplementation have been inconclusive. The WHO is coordinating three large randomised trials in Ghana, India, and Tanzania (Neovita trials). We present the findings of the Neovita trial in Ghana. METHODS: This study was a population-based, individually randomised, double-blind, placebo-controlled trial in the Brong Ahafo region of Ghana. The trial participants were infants aged at least 2 h, identified at home or facilities on the day of birth or in the next 2 days, able to feed orally, and likely to stay in the study area for at least 6 months. They were randomly assigned (ratio 1:1) to receive either one oral dose of vitamin A (50,000 IU) or placebo immediately after recruitment. The research team and parents of the infants were masked to treatment assignment. Follow-up home visits were undertaken every 4 weeks, when data were recorded for deaths, facility use, and care seeking. The primary outcome was post-supplementation mortality to 6 months of age. Analysis was by intention to treat. Potential adverse events were recorded at 1 and 3 days after supplementation. This trial is registered with the Australian New Zealand Clinical Trials Registry (ANZCTR)CTRN12610000582055. FINDINGS: We assessed 26,414 livebirths for eligibility between Aug 16, 2010, and Nov 7, 2011. We recruited 22,955 newborn infants, with 11,474 randomly assigned to receive vitamin A and 11,481 to receive placebo. Loss to follow-up was low with vital status at 6 months of age reported for 22,698 (98·9%) infants. We recorded 278 post-supplementation deaths to 6 months of age in the vitamin A group (mortality risk 24·5 in 1000 supplemented infants) and 248 deaths in the placebo group (mortality risk 21·8 per 1000 supplemented infants), relative risk (RR) 1·12 (95% CI 0·95-1·33; p=0·183) and risk difference (RD) 2·66 (95% CI -1·25 to 6·57; p=0·18). Adverse events within 3 days of supplementation did not differ by trial group. 122 infants died in the first 3 days after supplementation; 70 (0·6%) in the vitamin A and 52 (0·5%) in the placebo group (risk ratio [RR] 1·35, 95% CI 0·94-1·93, p=0·102). 53 infants were reported to have a bulging fontanelle; 32 (0·3%) in the vitamin A group and 21 (0·2%) in the placebo group (RR 1·53, 0·88-2·62, p=0·130). INTERPRETATION: The results of this trial do not support inclusion of newborn vitamin A supplementation as a child survival strategy in Ghana. FUNDING: Bill & Melinda Gates Foundation grant to the WHO.

Vaccination timing of low-birth-weight infants in rural Ghana: a population-based, prospective cohort study.

OBJECTIVE: To investigate delays in first and third dose diphtheria-tetanus-pertussis (DTP1 and DTP3) vaccination in low-birth-weight infants in Ghana, and the associated determinants. METHODS: We used data from a large, population-based vitamin A trial in 2010-2013, with 22 955 enrolled infants. We measured vaccination rate and maternal and infant characteristics and compared three categories of low-birth-weight infants (2.0-2.4 kg; 1.5-1.9 kg; and < 1.5 kg) with infants weighing ≥ 2.5 kg. Poisson regression was used to calculate vaccination rate ratios for DTP1 at 10, 14 and 18 weeks after birth, and for DTP3 at 18, 22 and 24 weeks (equivalent to 1, 2 and 3 months after the respective vaccination due dates of 6 and 14 weeks). FINDINGS: Compared with non-low-birth-weight infants (n = 18 979), those with low birth weight (n = 3382) had an almost 40% lower DTP1 vaccination rate at age 10 weeks (adjusted rate ratio, aRR: 0.58; 95% confidence interval, CI: 0.43-0.77) and at age 18 weeks (aRR: 0.63; 95% CI: 0.50-0.80). Infants weighing 1.5-1.9 kg (n = 386) had vaccination rates approximately 25% lower than infants weighing ≥ 2.5 kg at these time points. Similar results were observed for DTP3. Lower maternal age, educational attainment and longer distance to the nearest health facility were associated with lower DTP1 and DTP3 vaccination rates. CONCLUSION: Low-birth-weight infants are a high-risk group for delayed vaccination in Ghana. Efforts to improve the vaccination of these infants are warranted, alongside further research to understand the reasons for the delays.

PATHOS: a phase II/III trial of risk-stratified, reduced intensity adjuvant treatment in patients undergoing transoral surgery for Human papillomavirus (HPV) positive oropharyngeal cancer.

BACKGROUND: Human papillomavirus-positive oropharyngeal squamous cell carcinoma is increasing in incidence worldwide. Current treatments are associated with high survival rates but often result in significant long-term toxicities. In particular, long-term dysphagia has a negative impact on patient quality of life and health. The aim of PATHOS is to determine whether reducing the intensity of adjuvant treatment after minimally invasive transoral surgery in this favourable prognosis disease will result in better long-term swallowing function whilst maintaining excellent disease-specific survival outcomes. METHODS/DESIGN: The study is a multicentre phase II/III randomised controlled trial for patients with biopsy-proven Human papillomavirus-positive oropharyngeal squamous cell cancer staged T1-T3 N0-N2b with a primary tumour that is resectable via a transoral approach. Following transoral surgery and neck dissection, patients are allocated into three groups based on pathological risk factors for recurrence. Patients in the low-risk pathology group will receive no adjuvant treatment, as in standard practice. Patients in the intermediate-risk pathology group will be randomised to receive either standard dose post-operative radiotherapy (control) or reduced dose radiotherapy. Patients in the high-risk pathology group will be randomised to receive either post-operative chemoradiotherapy (control) or radiotherapy alone. The primary outcome of the phase II study is patient reported swallowing function measured using the MD Anderson Dysphagia Inventory score at 12 months post-treatment. If the phase II study is successful, PATHOS will proceed to a phase III non-inferiority trial with overall survival as the primary endpoint. DISCUSSION: PATHOS is a prospective, randomised trial for Human papillomavirus-positive oropharyngeal cancer, which represents a different disease entity compared with other head and neck cancers. The trial aims to demonstrate that long-term dysphagia can be lessened by reducing the intensity of adjuvant treatment without having a negative impact on clinical outcome. The study will standardise transoral surgery and post-operative intensity-modulated radiotherapy protocols in the UK and develop a gold-standard swallowing assessment panel. An associated planned translational research programme, underpinned by tumour specimens and sequential blood collected as part of PATHOS, will facilitate further empirical understanding of this new disease and its response to treatment. TRIAL REGISTRATION: This study is registered with ClinicalTrials.gov identifier NCT02215265 .

Effect of vitamin A supplementation on cause-specific mortality in women of reproductive age in Ghana: a secondary analysis from the ObaapaVitA trial.

OBJECTIVE: To determine the effect of weekly low-dose vitamin A supplementation on cause-specific mortality in women of reproductive age in Ghana. METHODS: A cluster-randomized, triple-blind, placebo-controlled trial was conducted in seven districts of the Brong Ahafo region of Ghana. Women aged 15-45 years who were capable of giving informed consent and intended to live in the trial area for at least 3 months were enrolled and randomly assigned, according to their cluster of residence, to receive oral vitamin A (7500 µg) or placebo once a week. Randomization was blocked, with two clusters in each fieldwork area allocated to vitamin A and two to placebo. Every 4 weeks, fieldworkers distributed capsules and collected data during home visits. Verbal autopsies were conducted by field supervisors and reviewed by physicians, who assigned a cause of death. Cause-specific mortality rates in both arms were compared by means of random-effects Poisson regression models to allow for the cluster randomization. Analysis was by intention-to-treat, based on cluster of residence, with women eligible for inclusion once they had consistently received the supplement or placebo capsules for 6 months. FINDINGS: The analysis was based on 581 870 woman-years and 2624 deaths. Cause-specific mortality rates were found to be similar in the two study arms. CONCLUSION: Low-dose vitamin A supplements administered weekly are of no benefit in programmes to reduce mortality in women of childbearing age.

Résumé OBJECTIF: Déterminer l'effet de la supplémentation hebdomadaire en vitamine A à faible dose sur la mortalité spécifique des femmes en âge de procréer au Ghana. MÉTHODES: Une étude randomisée, en triple aveugle, contrôlée contre placebo, a été menée dans sept districts de la région de Brong Ahafo au Ghana. Les femmes âgées de 15 à 45 ans, capables de donner un consentement éclairé et amenées à vivre dans la région de l'étude pendant au moins 3 mois, ont été incluses et il a été déterminé qu'elles recevraient une fois par semaine, au hasard selon leur groupe de résidence, de la vitamine A par voie orale (7 500 µg) ou un placebo. La randomisation a été fixée par deux groupes dans chaque zone recevant la vitamine A et deux groupes recevant le placebo. Toutes les 4 semaines, les agents de terrain distribuaient les capsules et recueillaient les données lors de visites à domicile. Des autopsies orales ont été effectuées par les superviseurs sur le terrain et analysées par des médecins, qui déterminaient la cause du décès. Les taux de mortalité spécifique dans les deux groupes ont été comparés à l'aide d'une régression de Poisson pour valider la randomisation des groupes. L'analyse, basée sur l'intention de traiter, était basée sur le groupe de résidence, pour des femmes éligibles à l'étude ayant reçu les capsules de supplément ou de placebo de manière constante pendant 6 mois. RÉSULTATS: L'analyse s'est basée sur 581 870 années-femmes et 2624 décès. Les taux de mortalité spécifique ont été jugés similaires dans les deux groupes de l'étude. CONCLUSION: Les suppléments en vitamine A à faible dose administrés hebdomadairement ne sont d'aucune utilité dans les programmes visant à réduire la mortalité chez les femmes en âge de procréer.

Resumen OBJETIVO: Determinar el efecto de la administración semanal de dosis bajas de vitamina A en la mortalidad por causas específicas de mujeres en edad reproductiva en Ghana. MÉTODOS: Se realizó un ensayo aleatorio de grupos, triple ciego y controlado por placebo en siete distritos de la región de Brong Ahafo, en Ghana. Se inscribieron mujeres de entre 15 y 45 años de edad capaces de dar su consentimiento informado y que tuvieran previsto vivir en el área de ensayo durante al menos tres meses. De acuerdo con el grupo de residencia al que habían sido asignadas de forma aleatoria, recibieron semanalmente vitamina A por vía oral (7500 µg) o placebo. La distribución aleatoria se limitó en cada área de trabajo a dos grupos a los que se les administró vitamina A y dos grupos que recibieron placebo. Cada cuatro semanas, los investigadores de campo distribuyeron cápsulas y recogieron datos durante las visitas a los hogares. Las autopsias verbales realizadas por los supervisores de campo fueron revisadas por médicos, quienes determinaron la causa de la muerte. Se compararon las tasas de mortalidad por causas específicas de ambos brazos mediante los modelos de regresión de Poisson con efectos aleatorios para facilitar la distribución aleatoria de los grupos. El análisis fue por intención de tratar, según el grupo de residencia y con mujeres que cumplieron las condiciones de inclusión una vez habían recibido de forma constante las cápsulas de suplemento o placebo durante seis meses. RESULTADOS: El análisis se basó en 581 870 años-mujer y 2624 muertes. Se descubrió que las tasas de mortalidad por causas específicas fueron similares en ambos brazos del estudio. CONCLUSIÓN: Los suplementos de dosis bajas de vitamina A administrados semanalmente no presentan ninguna ventaja en los programas para reducir la mortalidad de las mujeres en edad reproductiva.

A Road Map for Designing Phase I Clinical Trials of Radiotherapy-Novel Agent Combinations.

Radiotherapy has proven efficacy in a wide range of cancers. There is growing interest in evaluating radiotherapy-novel agent combinations and a drive to initiate this earlier in the clinical development of the novel agent, where the scientific rationale and preclinical evidence for a radiotherapy combination approach are high. Optimal design, delivery, and interpretation of studies are essential. In particular, the design of phase I studies to determine safety and dosing is critical to an efficient development strategy. There is significant interest in early-phase research among scientific and clinical communities over recent years, at a time when the scrutiny of the trial methodology has significantly increased. To enhance trial design, optimize safety, and promote efficient trial conduct, this position paper reviews the current phase I trial design landscape. Key design characteristics extracted from 37 methodology papers were used to define a road map and a design selection process for phase I radiotherapy-novel agent trials. Design selection is based on single- or dual-therapy dose escalation, dose-limiting toxicity categorization, maximum tolerated dose determination, subgroup evaluation, software availability, and design performance. Fifteen of the 37 designs were identified as being immediately accessible and relevant to radiotherapy-novel agent phase I trials. Applied examples of using the road map are presented. Developing these studies is intensive, highlighting the need for funding and statistical input early in the trial development to ensure appropriate design and implementation from the outset. The application of this road map will improve the design of phase I radiotherapy-novel agent combination trials, enabling a more efficient development pathway.

Effect of vitamin A supplementation in women of reproductive age on maternal survival in Ghana (ObaapaVitA): a cluster-randomised, placebo-controlled trial.

BACKGROUND: A previous trial in Nepal showed that supplementation with vitamin A or its precursor (betacarotene) in women of reproductive age reduced pregnancy-related mortality by 44% (95% CI 16-63). We assessed the effect of vitamin A supplementation in women in Ghana. METHODS: ObaapaVitA was a cluster-randomised, double-blind, placebo-controlled trial undertaken in seven districts in Brong Ahafo Region in Ghana. The trial area was divided into 1086 small geographical clusters of compounds with fieldwork areas consisting of four contiguous clusters. All women of reproductive age (15-45 years) who gave informed consent and who planned to remain in the area for at least 3 months were recruited. Participants were randomly assigned by cluster of residence to receive a vitamin A supplement (25 000 IU retinol equivalents) or placebo capsule orally once every week. Randomisation was blocked and based on an independent, computer-generated list of numbers, with two clusters in each fieldwork area allocated to vitamin A supplementation and two to placebo. Capsules were distributed during home visits undertaken every 4 weeks, when data were gathered on pregnancies, births, and deaths. Primary outcomes were pregnancy-related mortality and all-cause female mortality. Cause of death was established by verbal post mortems. Analysis was by intention to treat (ITT) with random-effects regression to account for the cluster-randomised design. Adverse events were synonymous with the trial outcomes. This trial is registered with ClinicalTrials.gov, number NCT00211341. FINDINGS: 544 clusters (104 484 women) were randomly assigned to vitamin A supplementation and 542 clusters (103 297 women) were assigned to placebo. The main reason for participant drop out was migration out of the study area. In the ITT analysis, there were 39 601 pregnancies and 138 pregnancy-related deaths in the vitamin A supplementation group (348 deaths per 100 000 pregnancies) compared with 39 234 pregnancies and 148 pregnancy-related deaths in the placebo group (377 per 100 000 pregnancies); adjusted odds ratio 0.92, 95% CI 0.73-1.17; p=0.51. 1326 women died in 292 560 woman-years in the vitamin A supplementation group (453 deaths per 100 000 years) compared with 1298 deaths in 289 310 woman-years in the placebo group (449 per 100 000 years); adjusted rate ratio 1.01, 0.93-1.09; p=0.85. INTERPRETATION: The body of evidence, although limited, does not support inclusion of vitamin A supplementation for women in either safe motherhood or child survival strategies. FUNDING: UK Department for International Development, and USAID.

Medullary Thyroid Cancer Patient's Assessment of Quality of Life Tools: Results from the QaLM Study.

BACKGROUND: Medullary thyroid cancer (MTC) is a neuroendocrine tumour and a rare variant of thyroid cancer with different aetiology, presentation and treatment to differentiated thyroid cancer. Currently available thyroid cancer-specific quality of life (QoL) tools focus on issues and treatments more relevant to patients with differentiated thyroid cancer and therefore may not address issues specific to a MTC diagnosis and cancer journey. METHOD: This prospective multicentre randomised study involved 204 MTC patients completing four quality of life questionnaires (QOLQ) and stating their most and least preferred. The questionnaires were a general instrument, the EORTC QLQ-C30, two disease-specific tools, the MD Anderson Symptom Inventory (MDASI) thyroid module and the City of Hope Quality of Life Scale/THYROID (amended) and the neuroendocrine questionnaire, EORTC QLQ-GINET21. Patients were randomised to complete the four questionnaires in one of 24 possible orders and then answered questions about which tool they preferred. The primary outcome measure was patients' preferred QoL instrument for describing their concerns and for facilitating communication with their healthcare professional. Secondary analyses looked at differences between preferred QOLQs amongst patient subgroups (WHO performance status [0 and 1+], disease stage: early [T1-3, N0 or N1A], metastatic [T4, any T N1b] and advanced [any T any N M1], and type of MTC [sporadic and inherited]), identification of MTC patients' least preferred questionnaire and clinicians' views on the QoL tools in terms of their ability to highlight problems not otherwise ascertained by a standard clinical review. RESULTS: No evidence of a difference was observed for most preferred QOLQ (p = 0.650). There was however evidence of a difference in least preferred questionnaire in the cohort of 128 patients who stated their least preferred questionnaire (p = 0.042), with 36% (46/128) of patients choosing the EORTC QLQ-GI.NET21 questionnaire. Subgroup analyses showed that there was no evidence of a difference in patients' most preferred questionnaire in sporadic MTC patients (p = 0.637), patients with WHO PS 0 or 1+ (p = 0.844 and p = 0.423) nor when comparing patients with early, advanced local or metastatic disease (p = 0.132, p = 0.463 and p = 0.506, respectively). Similarly, subgroup analyses on patients' least preferred questionnaires showed no evidence of differences in sporadic MTC patients (p = 0.092), patients with WHO PS 0 or 1+ (p = 0.423 and p = 0.276), nor in early or metastatic disease patients (p = 0.682 and p = 0.345, respectively). There was however some evidence to suggest a difference in least preferred questionnaire in patients with advanced local stage disease (p = 0.059), with 43% (16/37) of these patients choosing the EORTC QLQ-GI.NET21 questionnaire. CONCLUSIONS: MTC patients regardless of their performance status, disease aetiology and disease burden did not express a preference for any one particular questionnaire suggesting any of the tools studied could be utilized in this patient cohort. The least preferred questionnaire being a gastrointestinal NET specific tool suggests that diarrhoea was not a significant symptom and concern for the population studied.

Pentraxin 3 is a stromally-derived biomarker for detection of pancreatic ductal adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDAC), characterized by dense desmoplastic stroma laid down by pancreatic stellate cells (PSC), has no reliable diagnostic biomarkers for timely detection. A multi-center cohort of PDAC patients and controls (chronic pancreatitis, intra-ductal papillary neoplasms, gallstones and otherwise healthy) donated serum in an ethically approved manner. Serum PTX3 above 4.34 ng/mL has a higher sensitivity (86%, 95% confidence interval (CI): 65-97%) and specificity (86%, 95% CI: 79-91%), positive predictive value (97%) and likelihood ratio (6.05), and is superior when compared to serum CA19-9 and CEA for detection of PDAC. In vitro and ex vivo analyses of PTX3, in human PDAC samples, PSCs, cell lines and transgenic mouse model for PDAC, suggest that PTX3 originates from stromal cells, mainly PSC. In activated PSC, PTX3 secretion could be downregulated by rendering PSC quiescent using all-trans-retinoic acid (ATRA). PTX3 organizes hyaluronan in conjunction with tumor necrosis factor-stimulated gene 6 (TSG-6) and facilitates stellate and cancer cell invasion. In SCALOP clinical trial (ISRCTN96169987) testing chemo-radiotherapy without stromal targeting, PTX3 had no prognostic or predictive role. However, in STARPAC clinical trial (NCT03307148), stromal modulation by ATRA even at first dose is accompanied with serum PTX3 response in patients who later go on to demonstrate disease control but not those in whom the disease progresses. PTX3 is a putative stromally-derived biomarker for PDAC which warrants further testing in prospective, larger, multi-center cohorts and within clinical trials targeting stroma.

Deintensification of Adjuvant Treatment After Transoral Surgery in Patients With Human Papillomavirus-Positive Oropharyngeal Cancer: The Conception of the PATHOS Study and Its Development.

PATHOS is a phase II/III randomized controlled trial (RCT) of risk-stratified, reduced intensity adjuvant treatment in patients undergoing transoral surgery (TOS) for human papillomavirus (HPV)-positive oropharyngeal squamous cell carcinoma (OPSCC). The study opened in the UK in October 2015 and, after successful recruitment into the phase II, transitioned into phase III in the autumn of 2018. PATHOS aims to establish whether the de-intensification of adjuvant treatment in patients with favorable prognosis HPV-positive OPSCC will confer improved swallowing outcomes, whilst maintaining high rates of cure. In this article, we will outline the rationale for the study and how it aims to answer fundamentally important questions about the safety, effectiveness and functional outcomes of minimally invasive TOS techniques followed by adjuvant radiotherapy (RT) or chemo-radiotherapy (CRT) in this patient population.

Discovery of stable and prognostic CT-based radiomic features independent of contrast administration and dimensionality in oesophageal cancer.

The aim of this work was to investigate radiomic analysis of contrast and non-contrast enhanced planning CT images of oesophageal cancer (OC) patients in terms of stability, dimensionality and contrast agent dependency. The prognostic significance of CT-based radiomic features was also evaluated. Different 2D and 3D radiomic features were extracted from contrast and non-contrast enhanced CT images of 213 patients from the multi-centre SCOPE1 randomised controlled trial (RCT) in OC. Feature stability was evaluated by randomly dividing patients into three groups and identifying textures with similar distributions among groups with a Kruskal-Wallis analysis. A paired two-sided Wilcoxon signed rank test was used to assess for significant differences in the remaining corresponding 2D and 3D stable features. A prognostic model was constructed using clinical characteristics and remaining filtered features. The discriminative ability of significant variables was tested using Kaplan-Meier analysis. A total of 238 2D and 3D radiomic features were computed from oesophageal CT images. More than 75 features were stable if extracted from homogeneous cohort (contrast or non-contrast enhanced CT images) and inhomogeneous cohort (contrast and non-contrast enhanced CT images). Among the remaining corresponding stable features computed from both cohorts, only 4 features did not show a statistically significant difference if obtained in 2D or in 3D (p-value < 0.05). A Cox regression model constructed using 5 clinical variables (age, sex, tumour, node and metastasis (TNM) stage, WHO performance status and contrast administration) and 4 radiomic variables (inverse varianceGLCM, large distance emphasisGLDZM, zone distance non uniformity normGLDZM, zone distance varianceGLDZM), identified one radiomic feature (zone distance varianceGLDZM) that was significantly associated with overall survival (p-value = 0.032, HR = 1.25, 95% CI = 1.02-1.52). A significant difference in overall survival between groups was found when considering a threshold of zone distance varianceGLDZM equals to 1.70 (X2 = 7.692, df = 1, p-value = 0.006). Zone distance varianceGLDZM was identified as the only stable CT radiomic feature statistically correlated with overall survival, independent of dimensionality and contrast administration. This feature was able to identify high-risk patients and if validated, could be the subject of a future clinical trial aiming to improve clinical decision making and personalise OC treatment.

Feasibility and economic assessment of chromocolonoscopy for detection of proximal serrated neoplasia within a population-based colorectal cancer screening programme (CONSCOP): an open-label, randomised controlled non-inferiority trial.

BACKGROUND: Most post-colonoscopy interval colorectal cancers are proximal; serrated polyps are often precursors to these cancers and are considered difficult to detect. We assessed the safety, feasibility, and economic effect of chromocolonoscopy on detection of proximal serrated neoplasia. METHODS: We did an open-label, multicentre, randomised, controlled non-inferiority trial including patients from Bowel Screening Wales centres. Participants who tested positive for faecal occult blood and who were eligible for and considered fit to have colonoscopy (patients with known cases of polyposis syndromes, Lynch syndrome, and chronic inflammatory disease were excluded) were randomly assigned (1:1; with the use of minimisation, stratified by centre with an 80:20 random element) to either standard white light colonoscopy (standard group) or chromocolonoscopy (indigo carmine dye [0·2%]; chromocolonoscopy group) using a secure, internet-based, computerised, randomisation system that used centralised, dynamic allocation. Participants were followed up for 1 year and data from index colonoscopies and associated clearance procedures were analysed. All proximal polyps were reviewed by an expert pathologist panel. The main outcome on which power was based was time taken to perform the colonoscopy procedure, defined as from the time when the scope was inserted to withdrawal from the anus, assessed in the per-protocol population. The non-inferiority margin was 15 min. This trial is complete and is registered with ClinicalTrials.gov, number NCT01972451. FINDINGS: Between Nov 20, 2014, and June 16, 2016, 741 (72%) of 1031 patients screened were eligible and consented: 360 were randomly assigned to white light colonoscopy and 381 to chromocolonoscopy. In the chromocolonoscopy group, the procedure took a mean of 36·8 min (SD 15·0), compared with a mean of 30·6 min (13·7) in the standard group (mean difference 6·3 min [95% CI 4·2-8·4] longer with chromocolonoscopy than in the standard group). The mean difference was within the prespecified non-inferiority margin. Detection rates for proximal serrated lesions were significantly higher in the chromocolonoscopy group than in the control group (45 [12%] of 381 patients vs 23 [6%] of 360 patients; odds ratio 1·96 [95% CI 1·16-3·32]; p=0·012). Serious adverse events (four cases of postpolypectomy bleeding [two in each group], and one case of anxiety and hyperventilation [in the chromocolonoscopy group]), colonoscopy quality measures, comfort scores, and sedation were similar between groups. INTERPRETATION: Chromocolonoscopy is feasible within a population-based colorectal cancer screening programme, is safe, and has significantly increased detection of proximal serrated neoplasia and other polyp types compared with standard colonoscopy. Larger randomised trials of chromocolonoscopy, powered for improved detection of significant serrated polyps and for longer-term follow-up to investigate the effect on reduction of interval cancers within screening populations, are warranted. FUNDING: Health and Care Research Wales (RfPPB-1021).

Diagnostic accuracy of verbal autopsies in ascertaining the causes of stillbirths and neonatal deaths in rural Ghana.

This study evaluated the diagnostic accuracy of a verbal autopsy (VA) tool in ascertaining the causes of stillbirths and neonatal deaths in rural Ghana and was nested within a community-based maternal vitamin A supplementation trial (ObaapaVitA trial). All stillbirths and neonatal deaths between 1 January 2003 and 30 June 2004 were prospectively included. Community VAs were carried out within 6 months of death and were classified with a primary cause of death by three experienced paediatricans. The reference standard diagnosis was obtained by the study paediatrician in 4 district hospitals in the study area. There were 20,317 deliveries, 661 stillbirths and 590 neonatal deaths with a VA diagnosis in the study population. A total of 311 stillbirths and 191 neonatal deaths had both a VA and a hospital reference standard diagnosis. The VA performed poorly for stillbirth diagnoses such as congenital abnormalities and maternal haemorrhage. Accuracy was higher for intrapartum obstetric complications and antepartum maternal disease. For neonatal deaths, sensitivity was >60% for all major causes; specificity was 76% for birth asphyxia but >85% for prematurity and infection. Overall, VA diagnostic accuracy was higher than expected in this rural African setting. Our classification system was based on the expected public health importance of the individual causes of death, differing implications for intervention and the ability to distinguish between the individual causes in low-resource settings. We believe this system was easier to use than traditional approaches and resulted in high precision and accuracy. However, further simplifications are needed to allow use of the World Health Organisation VA in routine child health programmes. The diagnostic accuracy of the VA tool should also be assessed in other regions and in multicentre studies.

Aetiology of stillbirths and neonatal deaths in rural Ghana: implications for health programming in developing countries.

In developing countries many stillbirths and neonatal deaths occur at home and cause of death is not recorded by national health information systems. A community-level verbal autopsy tool was used to obtain data on the aetiology of stillbirths and neonatal deaths in rural Ghana. Objectives were to describe the timing and distribution of causes of stillbirths and neonatal deaths according to site of death (health facility or home). Data were collected from 1 January 2003 to 30 June 2004; 20,317 deliveries, 696 stillbirths and 623 neonatal deaths occurred over that time. Most deaths occurred in the antepartum period (28 weeks gestation to the onset of labour) (33.0%). However, the highest risk periods were during labour and delivery (intrapartum period) and the first day of life. Infections were a major cause of death in the antepartum (10.1%) and neonatal (40.3%) periods. The most important cause of intrapartum death was obstetric complications (59.3%). There were significantly fewer neonatal deaths resulting from birth asphyxia in the home than in the health facilities and more deaths from infection. Only 59 (20.7%) mothers of neonates who died at home reported that they sought care from an appropriate health care provider (doctor, nurse or health facility) during their baby's illness. The results from this study highlight the importance of studying community-level data in developing countries and the high risk of intrapartum stillbirths and infectious diseases in the rural African mother and neonate. Community-level interventions are urgently needed, especially interventions that reduce intrapartum deaths and infection rates in the mother and infant.