Tamoxifen is not effective in good prognosis patients with hepatocellular carcinoma

BACKGROUND: Large randomised clinical trials and systematic reviews substantiate that tamoxifen is ineffective in improving survival of patients with hepatocellular carcinoma (HCC). However, a recent report suggested that the drug might prolong survival among patients with well preserved liver function. The aim of this paper is to validate this hypothesis. METHODS: We used the updated database of the phase 3 randomised CLIP-1 trial that compared tamoxifen with supportive therapy. Primary endpoint was overall survival. Treatment arms were compared within strata defined according to the Okuda stage and the CLIP-score. Survival differences were tested by the Log-rank test. RESULTS: Tamoxifen was not effective in prolonging survival in Okuda I-II subgroup (p = 0.501). Median survival times were equal to 16.8 (95%CI 12.7–18.5) months for tamoxifen and 16.8 (95%CI 13.5–22.4) months for the control arms; 1-year survival probabilities were equal to 58.8% (95%CI 51.7–65.8) and 59.4 (95%CI 52.5–66.2), respectively. Similar results were observed in the better CLIP subgroup (score 0/1), without evidence of difference between the two treatment arms (p = 0.734). Median survival times were equal to 29.2 (95%CI 20.1–36.4) months with tamoxifen and 29.0 (95%CI 23.3–35.2) months without; 1-year survival probabilities were equal to 80.9% (95%CI 72.5–89.3) with tamoxifen and 77.1% (95%CI 68.6–85.7) for the control arm. CONCLUSION: The recent suggestion that tamoxifen might be effective in the subgroup of patients with better prognosis is not supported by a reanalysis of the CLIP-1 trial. Tamoxifen should no longer be considered for the treatment of HCC patients and future trials of medical treatment should concentrate on different drugs

The community-level interventions for pre-eclampsia (CLIP) cluster randomised trials in Mozambique, Pakistan, and India: An individual participant-level meta-analysis

Background: To overcome the three delays in triage, transport and treatment that underlie adverse pregnancy outcomes, we aimed to reduce all-cause adverse outcomes with community-level interventions targeting women with pregnancy hypertension in three low-income countries.Methods: In this individual participant-level meta-analysis, we de-identified and pooled data from the Community-Level Interventions for Pre-eclampsia (CLIP) cluster randomised controlled trials in Mozambique, Pakistan, and India, which were run in 2014-17. Consenting pregnant women, aged 12-49 years, were recruited in their homes. Clusters, defined by local administrative units, were randomly assigned (1:1) to intervention or control groups. The control groups continued local standard of care. The intervention comprised community engagement and existing community health worker-led mobile health-supported early detection, initial treatment, and hospital referral of women with hypertension. For this meta-analysis, as for the original studies, the primary outcome was a composite of maternal or perinatal outcome (either maternal, fetal, or neonatal death, or severe morbidity for the mother or baby), assessed by unmasked trial surveillance personnel. For this analysis, we included all consenting participants who were followed up with completed pregnancies at trial end. We analysed the outcome data with multilevel modelling and present data with the summary statistic of adjusted odds ratios (ORs) with 95% CIs (fixed effects for maternal age, parity, maternal education, and random effects for country and cluster). This meta-analysis is registered with PROSPERO, CRD42018102564.Findings: Overall, 44 clusters (69 330 pregnant women) were randomly assigned to intervention (22 clusters [36 008 pregnancies]) or control (22 clusters [33 322 pregnancies]) groups. 32 290 (89·7%) pregnancies in the intervention group and 29 698 (89·1%) in the control group were followed up successfully. Median maternal age of included women was 26 years (IQR 22-30). In the intervention clusters, 6990 group and 16 691 home-based community engagement sessions and 138 347 community health worker-led visits to 20 819 (57·8%) of 36 008 women (of whom 11 095 [53·3%] had a visit every 4 weeks) occurred. Blood pressure and dipstick proteinuria were assessed per protocol. Few women were eligible for methyldopa for severe hypertension (181 [1%] of 20 819) or intramuscular magnesium sulfate for pre-eclampsia (198 [1%]), of whom most accepted treatment (162 [89·5%] of 181 for severe hypertension and 133 [67·2%] of 198 for pre-eclampsia). 1255 (6%) were referred to a comprehensive emergency obstetric care facility, of whom 864 (82%) accepted the referral. The primary outcome was similar in the intervention (7871 [24%] of 32 290 pregnancies) and control clusters (6516 [22%] of 29 698; adjusted OR 1·17, 95% CI 0·90-1·51; p=0·24). No intervention-related serious adverse events occurred, and few adverse effects occurred after in-community treatment with methyldopa (one [2%] of 51; India only) and none occurred after in-community treatment with magnesium sulfate or during transport to facility.Interpretation: The CLIP intervention did not reduce adverse pregnancy outcomes. Future community-level interventions should expand the community health worker workforce, assess general (rather than condition-specific) messaging, and include health system strengthening.Funding: University of British Columbia, a grantee of the Bill & Melinda Gates Foundation

Transitioning from the “Three Delays” to a focus on continuity of care: a qualitative analysis of maternal deaths in rural Pakistan and Mozambique

Background: The Three Delays Framework was instrumental in the reduction of maternal mortality leading up to, and during the Millennium Development Goals. However, this paper suggests the original framework might be reconsidered, now that most mothers give birth in facilities, the quality and continuity of the clinical care is of growing importance. Methods: The paper explores the factors that contributed to maternal deaths in rural Pakistan and Mozambique, using 76 verbal autopsy narratives from the Community Level Interventions for Pre-eclampsia (CLIP) Trial. Results: Qualitative analysis of these maternal death narratives in both countries reveals an interplay of various influences, such as, underlying risks and comorbidities, temporary improvements after seeking care, gaps in quality care in emergencies, convoluted referral systems, and arrival at the final facility in critical condition. Evaluation of these narratives helps to reframe the pathways of maternal mortality beyond a single journey of care-seeking, to update the categories of seeking, reaching and receiving care. Conclusions: There is a need to supplement the pioneering “Three Delays Framework” to include focusing on continuity of care and the “Four Critical Connection Points”: (1) between the stages of pregnancy, (2) between families and health care workers, (3) between health care facilities and (4) between multiple care-seeking journeys. Trial registration: NCT01911494, Date Registered 30/07/2013

Maternal and Newborn Health in Karnataka State, India:The Community Level Interventions for Pre-Eclampsia (CLIP) Trial’s Baseline Study Results

Existing vital health statistics registries in India have been unable to provide reliable estimates of maternal and newborn mortality and morbidity, and region-specific health estimates are essential to the planning and monitoring of health interventions. This study was designed to assess baseline rates as the precursor to a community-based cluster randomized control trial (cRCT)–Community Level Interventions for Pre-eclampsia (CLIP) Trial (NCT01911494; CTRI/2014/01/004352). The objective was to describe baseline demographics and health outcomes prior to initiation of the CLIP trial and to improve knowledge of population-level health, in particular of maternal and neonatal outcomes related to hypertensive disorders of pregnancy, in northern districts the state of Karnataka, India. The prospective population-based survey was conducted in eight clusters in Belgaum and Bagalkot districts in Karnataka State from 2013–2014. Data collection was undertaken by adapting the Maternal and Newborn Health registry platform, developed by the Global Network for Women’s and Child Health Studies. Descriptive statistics were completed using SAS and R. During the period of 2013–2014, prospective data was collected on 5,469 pregnant women with an average age of 23.2 (+/-3.3) years. Delivery outcomes were collected from 5,448 completed pregnancies. A majority of the women reported institutional deliveries (96.0%), largely attended by skilled birth attendants. The maternal mortality ratio of 103 (per 100,000 livebirths) was observed during this study, neonatal mortality ratio was 25 per 1,000 livebirths, and perinatal mortality ratio was 50 per 1,000 livebirths. Despite a high number of institutional deliveries, rates of stillbirth were 2.86%. Early enrollment and close follow-up and monitoring procedures established by the Maternal and Newborn Health registry allowed for negligible lost to follow-up. This population-level study provides regional rates of maternal and newborn health in Belgaum and Bagalkot in Karnataka over 2013–14. The mortality ratios and morbidity information can be used in planning interventions and monitoring indicators of effectiveness to inform policy and practice. Comprehensive regional epidemiologic data, such as that provided here, is essential to gauge improvements and challenges in maternal health, as well as track disparities found in rural areas

Mothers' satisfaction with care during facility-based childbirth: a cross-sectional survey in southern Mozambique.

BACKGROUND: Client satisfaction is an essential component of quality of care. Health system factors, processes of care as well as mothers' characteristics influence the extent to which care meets the expectations of mothers and families. In our study, we specifically aimed to address the mothers' experiences of, and satisfaction with, care during childbirth. METHODS: A population-based cross-sectional study, using structured interviews with published sequences of questions assessing satisfaction, including 4358 mothers who gave birth during the 12 months before June 2016 to estimate satisfaction with childbirth care. Regression analysis was used to determine the predictors of client satisfaction. RESULTS: Most mothers (92.5%) reported being satisfied with care during childbirth and would recommend that a family member to deliver at the same facility. Specifically, 94.7% were satisfied with the cleanliness of the facility, 92.0% reported being satisfied with the interaction with the healthcare providers, but only 49.8% felt satisfied with the assistance to feed their baby. Mothers who had negative experiences during the process of care, such as being abandoned when needing help, disrespect, humiliation, or physical abuse, reported low levels of satisfaction when compared to those who had not had such experiences (68.5% vs 93.5%). Additionally, they reported higher levels of dissatisfaction (20.1% vs 2.1%). Regression analysis revealed that mothers who gave birth in primary level facilities tended to be more satisfied than those who gave birth in hospitals, and having a companion increased, on average, the overall satisfaction score, with 0.06 in type II health centres (CI 0.03-0.10) and with 0.05 in type I health centres (CI - 0.02 - 0.13), compared to - 0.01(CI -0.08 - 0.07) in the hospitals, irrespective of age, education and socio-economic background. CONCLUSION: Childbirth at the primary level facilities contributes to the level of satisfaction. The provision of childbirth care should consider women's preferences and needs, including having a companion of choice. We highlight the challenge in balancing safety of care versus satisfaction with care and in developing policies on the optimum configuration of childbirth care. Interventions to improve the interaction with providers and the provision of respectful care are recommended

Community health worker knowledge and management of pre-eclampsia in southern Mozambique

BACKGROUND: Mozambique has drastically improved an array of health indicators in recent years, including maternal mortality rates which decreased 63 % from 1990-2013 but the rates still high. Pre-eclampsia and eclampsia constitute the third major cause of maternal death in the country. Women in rural areas, with limited access to health facilities are at greatest risk. This study aimed to assess the current state of knowledge and the regular practices regarding pre-eclampsia and eclampsia by community health workers in southern Mozambique. METHODS: This mixed methods study was conducted from 2013 to 2014, in Maputo and Gaza Provinces, southern Mozambique. Self-administered questionnaires, in-depth interviews and focus group discussions were conducted with CHWs, district medical officers, community health workers' supervisors, Gynaecologists-Obstetricians and matrons. Quantitative data were entered into a database written in REDCap and subsequently analyzed using Stata 13. Qualitative data was imported into NVivo10 for thematic analysis. RESULTS: Ninety-three percent of CHW had some awareness of pregnancy complications. Forty-one percent were able to describe the signs and symptoms of hypertension. In cases of eclampsia, CHWs reported to immediately refer the women. The vast majority of the CHWs surveyed reported that they could neither measure blood pressure nor proteinuria (90 %). Fewer reported confidence in providing oral antihypertensives (14 %) or injections in pregnancy (5 %). The other community health care providers are matrons. They do not formally offer health services, but assists pregnant women in case of an emergency. Regarding pre-eclampsia and eclampsia, matrons were unable to recognise these biomedical terms. CONCLUSIONS: Although CHWs are aware of pregnancy complications, they hold limited knowledge specific to pre-eclampsia and eclampsia. There is a need to promote studies to evaluate the impact of enhancing their training to include additional content related to the identification and management of pre-eclampsia and eclampsia

The feasibility of task-sharing the identification, emergency treatment, and referral for women with pre-eclampsia by community health workers in India.

BACKGROUND: Hypertensive disorders are the second highest direct obstetric cause of maternal death after haemorrhage, accounting for 14% of maternal deaths globally. Pregnancy hypertension contributes to maternal deaths, particularly in low- and middle-income countries, due to a scarcity of doctors providing evidence-based emergency obstetric care. Task-sharing some obstetric responsibilities may help to reduce the mortality rates. This study was conducted to assess acceptability by the community and other healthcare providers, for task-sharing by community health workers (CHW) in the identification and initial care in hypertensive disorders in pregnancy. METHODS: This study was conducted in two districts of Karnataka state in south India. A total of 14 focus group discussions were convened with various community representatives: women of reproductive age (N = 6), male decision-makers (N = 2), female decision-makers (N = 3), and community leaders (N = 3). One-to-one interviews were held with medical officers (N = 2), private healthcare OBGYN specialists (N = 2), senior health administrators (N = 2), Taluka (county) health officers (N = 2), and obstetricians (N = 4). All data collection was facilitated by local researchers familiar with the setting and language. Data were subsequently transcribed, translated and analysed thematically using NVivo 10 software. RESULTS: There was strong community support for home visits by CHW to measure the blood pressure of pregnant women; however, respondents were concerned about their knowledge, training and effectiveness. The treatment with oral antihypertensive agents and magnesium sulphate in emergencies was accepted by community representatives but medical practitioners and health administrators had reservations, and insisted on emergency transport to a higher facility. The most important barriers for task-sharing were concerns regarding insufficient training, limited availability of medications, the questionable validity of blood pressure devices, and the ability of CHW to correctly diagnose and intervene in cases of hypertensive disorders of pregnancy. CONCLUSION: Task-sharing to community-based health workers has potential to facilitate early diagnosis of the hypertensive disorders of pregnancy and assist in the provision of emergency care. We identified some facilitators and barriers for successful task-sharing of emergency obstetric care aimed at reducing mortality and morbidity due to hypertensive disorders of pregnancy

Community Engagement for Birth Preparedness and Complication Readiness in the Community Level Interventions for Pre-eclampsia (CLIP) Trial in India: A Mixed-Method Evaluation

Objective: To describe the process of community engagement (CE) in northern Karnataka, India and its impact on pre-eclampsia knowledge, birth preparedness and complication readiness, pregnancy-related care seeking and maternal morbidity. Design: This study was a secondary analysis of a cluster randomised trial of Community Level Interventions for Pre-eclampsia (CLIP). A total of 12 clusters based on primary health centre catchment areas were randomised to intervention or control. CE was conducted in intervention clusters. CE attendance was summarised according to participant group using both quantitative and qualitative assessment. Pre-eclampsia knowledge, birth preparedness, health services engagement and perinatal outcomes was evaluated within trial surveillance. Outcomes were compared between trial arms using a mixed effects logistic regression model on RStudio (RStudio, Boston, USA). Community feedback notes were thematically analysed on NVivo V.12 (QSR International, Melbourne, Australia). Setting: Belagavi and Bagalkote districts in rural Karnataka, India. Participants: Pregnant women and women of reproductive age, mothers and mothers-in-law, community stakeholders and male household decision-makers and health workers. Results: A total of 1379 CE meetings were conducted with 39 362 participants between November 2014 and October 2016. CE activities may have had an effect on modifying community attitudes towards hypertension in pregnancy and its complications. However, rates of pre-eclampsia knowledge, birth preparedness, health services engagement and maternal morbidities among individual pregnant women were not significantly impacted by CE activities in their area. Conclusion: Evaluation of our CE programme in India demonstrates the feasibility of reaching pregnant women alongside household decision-makers, community stakeholders and health workers. More research is needed to explore the pathways of impact between broad community mobilisation to strengthen support for maternal care seeking and clinical outcomes of individual pregnant women. Trial registration number: NCT01911494

Efficacy of the combination of long-acting release octreotide and tamoxifen in patients with advanced hepatocellular carcinoma: a randomised multicentre phase III study

To assess the efficacy of the combination of long-acting release (LAR) octreotide and tamoxifen (TMX) for the treatment of advanced hepatocellular carcinoma (HCC). A total of 109 patients with advanced HCC were randomised to receive octreotide LAR combined with TMX (n=56) (experimental treatment group) or TMX alone (n=53; control group). The clinical, biological and tumoural parameters were recorded every 3 months until death. Primary end point was patient survival; secondary end points were the impact of therapy on tumour response, quality of life and variceal bleeding episodes. Univariate and multivariate analyses were performed for assessment of specific prognostic factors. The median survival was 3 months (95% CI 1.4–4.6) for the experimental treatment group and 6 months (CI 95% 2–10) for the control group (P=0.609). There was no difference in terms of α-foetoprotein (α-FP) decrease, tumour regression, improvement of quality of life and prevention of variceal bleeding between the two groups. Variables associated with a better survival in the multivariate analysis were: presence of cirrhosis, α-FP level <400 ng ml−1 and Okuda stage I. The combination of octreotide LAR and TMX does not influence survival, tumour progression or quality of life in patients with advanced HCC