Cancer Research UK.

SummaryBackgroundIn the UK, chemotherapy is the standard treatment for inoperable, locally advanced, non-metastatic pancreatic cancer. Chemoradiotherapy is also an acceptable treatment option, for which gemcitabine, fluorouracil, or capecitabine can be used as concurrent chemotherapy agents. We aimed to assess the activity, safety, and feasibility of both gemcitabine-based and capecitabine-based chemoradiotherapy after induction chemotherapy for patients with locally advanced pancreatic cancer.MethodsIn this open-label, randomised, two-arm, phase 2 trial, patients aged 18 years or older with histologically proven, locally advanced pancreatic cancer (with a tumour diameter of 7 cm or less) were recruited from 28 UK centres between Dec 24, 2009 and Oct 25, 2011. After 12 weeks of induction gemcitabine and capecitabine chemotherapy (three cycles of gemcitabine [1000 mg/m2 on days 1, 8, 15 of a 28-day cycle] and capecitabine [830 mg/m2 twice daily on days 1–21 of a 28-day cycle]), patients with stable or responding disease, tumour diameter of 6 cm or less, and WHO performance status 0–1 were randomly assigned to receive a further cycle of gemcitabine and capecitabine chemotherapy followed by either gemcitabine (300 mg/m2 once per week) or capecitabine (830 mg/m2 twice daily, Monday to Friday only), both in combination with radiation (50·4 Gy in 28 fractions). Randomisation (1:1) was done via a central computerised system and used stratified minimisation. The primary endpoint was 9-month progression-free survival, analysed by intention to treat including only those patients with valid CT assessments. This trial is registered with ISRCTN, number 96169987.Findings114 patients were registered and 74 were randomly allocated (38 to the gemcitabine group and 36 to the capecitabine group). After 9 months, 22 of 35 assessable patients (62·9%, 80% CI 50·6–73·9) in the capecitabine group and 18 of 35 assessable patients (51·4%, 39·4–63·4) in the gemcitabine group had not progressed. Median overall survival was 15·2 months (95% CI 13·9–19·2) in the capecitabine group and 13·4 months (95% CI 11·0–15·7) in the gemcitabine group (adjusted hazard ratio [HR] 0·39, 95% CI 0·18–0·81; p=0·012). 12-month overall survival was 79·2% (95% CI 61·1–89·5) in the capecitabine group and 64·2 (95% CI 46·4–77·5) in the gemcitabine group. Median progression-free survival was 12·0 months (95% CI 10·2–14·6) in the capecitabine group and 10·4 months (95% CI 8·9–12·5) in the gemcitabine group (adjusted HR 0·60, 95% CI 0·32–1·12; p=0·11). Eight patients in the capecitabine group had an objective response at 26 weeks, as did seven in the gemcitabine group. More patients in the gemcitabine group than in the capecitabine group had grade 3–4 haematological toxic effects (seven [18%] vs none, p=0·008) and non-haematological toxic effects (ten [26%] vs four [12%], p=0·12) during chemoradiation treatment; the most frequent events were leucopenia, neutropenia, and fatigue. Two patients in the capecitabine group progressed during the fourth cycle of induction ch...

Objective To investigate the risk of adverse birth outcomes associated with residence near landfill sites in Great Britain.

BackgroundHuman 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/DesignThe 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.DiscussionPATHOS 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 registrationThis study is registered with ClinicalTrials.gov identifier NCT02215265.

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.

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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.

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