The interrelationship between multiple long-term conditions (MLTC) and delirium: a scoping review.

INTRODUCTION: Delirium and multiple long-term conditions (MLTC) share numerous risk factors and have been shown individually to be associated with adverse outcomes following hospitalisation. However, the extent to which these common ageing syndromes have been studied together is unknown. This scoping review aims to summarise our knowledge to date on the interrelationship between MLTC and delirium. METHODS: Searches including terms for delirium and MLTC in adult human participants were performed in PubMed, EMBASE, Medline, Psycinfo and CINAHL. Descriptive analysis was used to summarise findings, structured according to Synthesis Without Meta-analysis reporting guidelines. RESULTS: After removing duplicates, 5256 abstracts were screened for eligibility, with 313 full-texts sought along with 17 additional full-texts from references in review articles. In total, 140 met inclusion criteria and were included in the final review. Much of the literature explored MLTC as a risk factor for delirium (n = 125). Fewer studies explored the impact of MLTC on delirium presentation (n = 5), duration (n = 3) or outcomes (n = 6) and no studies explored how MLTC impacts the treatment of delirium or whether having delirium increases risk of developing MLTC. The most frequently used measures of MLTC and delirium were the Charlson Comorbidity Index (n = 98/140) and Confusion Assessment Method (n = 81/140), respectively. CONCLUSION: Existing literature largely evaluates MLTC as a risk factor for delirium. Major knowledge gaps identified include the impact of MLTC on delirium treatment and the effect of delirium on MLTC trajectories. Current research in this field is limited by significant heterogeneity in defining both MLTC and delirium.

Creating Virtual Models and 3D Movies Using DemoMaker for Anatomical Education.

Three-dimensional (3D) anatomy models have been used for education in health professional schools globally. Virtual technology has become more popular for online teaching since the COVID-19 pandemic. This chapter will describe a project in which a series of virtual anatomical models of organs and structures were developed for educational purposes, and it will describe in detail how to build three-dimensional (3D) movies using DemoMaker. Although setting up the 3D system was complicated and challenging, the process of reconstructing 3D models from radiographic images and the steps of creating animations and 3D movies are exponentially simpler. These efforts require minimal training, thus allowing most people to be able to engage in this modeling process and utilize the moviemaking steps. Amira® software and computed tomographic angiography (CTA) data were used to create 3D models of the lungs, heart, liver, stomach, kidney, etc. The anatomical locations of these structures within the body can be identified and visualized by recording information from multiple CTA slices using volume and surface segmentation. Ultimately, these virtual 3D models can be displayed via dual projectors onto a specialized silver screen and visualized stereoscopically by viewers as long as they wear 3D polarized glasses. Once these 3D movies are created, they can be played automatically on a computer screen, silver screen, 3D system playback screen, and video player, and they can be embedded into PowerPoint lecture slides. Both virtual models and movies are suitable for self-directed learning, face-to-face class teaching, and virtual anatomy education. Model animations and 3D movie displays offer students the opportunities to learn about anatomy and the anatomical positions of organs in the body and their 3D relationships to one another. By observing and studying these 3D models, students have the potential to be able to compartmentalize the anatomical information and retain it at a higher level than students learning corresponding anatomy without similar resources.

Defective Monocyte Enzymatic Function and an Inhibitory Immune Phenotype in Human Immunodeficiency Virus-Exposed Uninfected African Infants in the Era of Antiretroviral Therapy.

BACKGROUND: Human immunodeficiency virus-exposed uninfected (HEU) infants are a rapidly expanding population in sub-Saharan Africa and are highly susceptible to encapsulated bacterial disease in the first year of life. The mechanism of this increased risk is still poorly understood. We investigated whether human immunodeficiency virus (HIV)-exposure dysregulates HEU immunity, vaccine-antibody production, and human herpes virus amplify this effect. METHODS: Thirty-four HIV-infected and 44 HIV-uninfected pregnant women were recruited into the birth cohort and observed up to 6 weeks of age; and then a subsequent 43 HIV-infected and 61 HIV-uninfected mother-infant pairs were recruited into a longitudinal infant cohort at either: 5-7 to 14-15; or 14-15 to 18-23 weeks of age. We compared monocyte function, innate and adaptive immune cell phenotype, and vaccine-induced antibody responses between HEU and HIV-unexposed uninfected (HU) infants. RESULTS: We demonstrate (1) altered monocyte phagosomal function and B-cell subset homeostasis and (2) lower vaccine-induced anti-Haemophilus influenzae type b (Hib) and anti-tetanus toxoid immunoglobulin G titers in HEU compared with HU infants. Human herpes virus infection was similar between HEU and HU infants. CONCLUSIONS: In the era of antiretroviral therapy-mediated viral suppression, HIV exposure may dysregulate monocyte and B-cell function, during the vulnerable period of immune maturation. This may contribute to the high rates of invasive bacterial disease and pneumonia in HEU infants.

Early T Cell Differentiation with Well-Maintained Function across the Adult Life Course in Sub-Saharan Africa.

Immune senescence is a significant contributor to health problems in the developed world and may be accelerated by chronic viral infections. To date, there have been few studies of immune function in healthy older people in sub-Saharan Africa. We assessed T cell and B cell phenotypes and immune responses to CMV, EBV, and influenza virus in Malawians aged 20-69 y. Notably, the proportion of naive (CCR7+CD45RA+) CD4 and CD8 T cells was only 14% of the lymphoid repertoire even in donors aged under 30 y but did not decrease further with age. A small increase in the late differentiated (CD27-CD28-) CD8 T cell subpopulation was observed in older donors but the CD4/CD8 T cell ratio remained stable in all age groups. Interestingly, the regulatory (CD25hiFOXP3hi) T cell subpopulation was small in all age groups, and we observed no age-associated accumulation of cells expressing the senescence- and exhaustion-associated markers CD57 and PD-1. We assessed functional T cell responses to mitogenic and viral antigenic stimulation by the expression of CD154, IFN-γ, TNF-α, IL-2, and IL-17 and proliferation. All responses were robust across the life course, although we observed an age-associated shift from IFN-γ to TNF-α in the response to EBV. In summary, we found the naive T cell subpopulation of young adult Malawians was smaller than in their contemporaries in high-income settings but remains stable thereafter and that lymphocyte function is retained across the life course. These observations indicate that studies of the genetic and environmental factors influencing immune function in different environments may provide insights into minimizing immune ageing.

Spontaneous Flares of Chronic Hepatitis B Virus in Hepatitis Be Antigen Negative Carriers Who Subsequently Clear Hepatitis B Surface Antigen.

BACKGROUND: Acute exacerbations of chronic hepatitis B virus (HBV) infections can occur in HBV-infected, hepatitis e antigen (HBeAg)-negative patients in the absence of recent withdrawal of antiviral or immunosuppressive therapies. Whether these spontaneous "flares" predict subsequent loss of hepatitis B surface antigen (HBsAg) has yet to be determined. OBJECTIVES: To document the percent of patients who experience spontaneous HBV flares and severity of the flares in chronic HBeAg-negative carriers. METHODS: A retrospective review of an HBV database identified and followed HBeAg-negative patients for biochemical evidence of flares (ALT > 5× normal) and subsequent HBsAg status. Patients that subsequently cleared HBsAg were matched 1:1 with those who remained HBsAg positive. RESULTS: Of 1299 HBeAg-negative patients followed for 10.2 ± 6.1 years, 88 (6.8%) developed spontaneous HBV flares. Flares occurred in 14/115 (12.2%) patients who subsequently cleared HBsAg and 4/111 (3.6%) matched patients who remained HBsAg positive (p = 0.025). The severity of flares was similar in the two study cohorts. Following multivariate analyses, only low HBV-DNA levels at baseline identified patients likely to subsequently clear HBsAg. CONCLUSIONS: Although more common in patients who subsequently clear HBsAg, spontaneous HBV flares do not predict subsequent HBsAg clearance.

How fast should social restrictions be eased in England as COVID-19 vaccinations are rolled out?

INTRODUCTION: Vaccination against the COVID-19 virus began in December 2020 in the UK and into Spring 2021 has been running at 5% population/week. High levels of social restrictions were implemented for the third time in January 2021 to control the second wave and resulting increases in hospitalisations and deaths. Easing those restrictions must balance multiple challenging priorities, weighing the risk of more deaths and hospitalisations against damage done to mental health, incomes and standards of living, education and provision of non-Covid-19 healthcare. METHODS: Weekly and monthly officially published data for 2020/21 were used to estimate the influence of seasonality and social restrictions on the spread of COVID-19 by age group, on the economy and on healthcare services. These factors were combined with the estimated impact of vaccinations and immunity from past infections into a model that retrospectively reflected the actual numbers of reported deaths closely both in 2020 and early 2021. The model was applied prospectively to the next 6 months to evaluate the impact of different speeds of easing social restrictions. RESULTS: The results show vaccinations as significantly reducing the number of hospitalisations and deaths. The central estimate is that relative to rapid easing, the avoided loss of 57 000 life-years from a strategy of relatively slow easing over the next several  months comes at a cost in terms of GDP reduction of around £0.4 million/life-year loss avoided. This is over 10 times higher than the usual limit the NHS uses for spending against Quality Adjusted Life Years (QALYs) saved. Alternative assumptions for key factors affecting the spread of the virus give significantly different trade-offs between costs and benefits of different speeds of easing. Disruption of non-Covid-19 Healthcare provision also increases in times of higher levels of social restrictions. CONCLUSION: In most cases, the results favour a somewhat faster easing of restrictions in England than current policy implies.

Assessing the spread of the novel coronavirus in the absence of mass testing.

BACKGROUND: Assessing why the spread of the COVID-19 virus slowed down in many countries in March through to May of 2020 is of great significance. The relative role of restrictions on behaviour ("lockdowns") and of a natural slowing for other reasons is difficult to assess when mass testing was not widely done. This paper assesses the evolution of the spread of the COVID-19 virus over this period when there was no data on test results for a large, random sample of the population. METHOD: We estimate a version of the susceptible-infected-recovered model applied to data on the numbers who were tested positive in several countries over the period when the virus spread very fast and then its spread slowed sharply. Up to the end of April 2020, test data came from non-random samples of populations who were overwhelmingly those who displayed symptoms. Using data from a period when the criteria used for testing (which was that people had clear symptoms) was relatively consistent is important in drawing out the message from test results. We use this data to assess two things: how large might be the group of those infected who were not recorded and how effective were lockdown measures in slowing the spread of the infection. RESULTS: We find that to match data on daily new cases of the virus, the estimated model favours high values for the number of people infected but not recorded. CONCLUSIONS: Our findings suggest that the infection may have spread far enough in many countries by April 2020 to have been a significant factor behind the fall in measured new cases. Government restrictions on behaviour-lockdowns-were only one factor behind slowing in the spread of the virus.

"Stay at Home, Protect the National Health Service, Save Lives": A cost benefit analysis of the lockdown in the United Kingdom.

INTRODUCTION: The COVID-19 pandemic has transformed lives across the world. In the UK, a public health driven policy of population "lockdown" has had enormous personal and economic impact. METHODS: We compare UK response and outcomes with European countries of similar income and healthcare resources. We calibrate estimates of the economic costs as different % loss in Gross Domestic Product (GDP) against possible benefits of avoiding life years lost, for different scenarios where current COVID-19 mortality and comorbidity rates were used to calculate the loss in life expectancy and adjusted for their levels of poor health and quality of life. We then apply a quality-adjusted life years (QALY) value of £30,000 (maximum under national guidelines). RESULTS: There was a rapid spread of cases and significant variation both in severity and timing of both implementation and subsequent reductions in social restrictions. There was less variation in the trajectory of mortality rates and excess deaths, which have fallen across all countries during May/June 2020. The average age at death and life expectancy loss for non-COVID-19 was 79.1 and 11.4 years, respectively, while COVID-19 were 80.4 and 10.1 years; including adjustments for life-shortening comorbidities and quality of life plausibly reduces this to around 5 QALY lost for each COVID-19 death. The lowest estimate for lockdown costs incurred was 40% higher than highest benefits from avoiding the worst mortality case scenario at full life expectancy tariff and in more realistic estimations they were over 5 times higher. Future scenarios showed in the best case a QALY value of £220k (7xNICE guideline) and in the worst-case £3.7m (125xNICE guideline) was needed to justify the continuation of lockdown. CONCLUSION: This suggests that the costs of continuing severe restrictions are so great relative to likely benefits in lives saved that a rapid easing in restrictions is now warranted.

Pertuzumab, trastuzumab, and docetaxel for HER2-positive metastatic breast cancer (CLEOPATRA): end-of-study results from a double-blind, randomised, placebo-controlled, phase 3 study.

BACKGROUND: CLEOPATRA was a phase 3 study comparing the efficacy and safety of pertuzumab, trastuzumab, and docetaxel with placebo, trastuzumab, and docetaxel in patients with HER2-positive metastatic breast cancer. In the primary analysis and subsequent reports, progression-free and overall survival were significantly improved in the pertuzumab group compared with the placebo group. Here, we report the end-of-study analysis of CLEOPATRA. METHODS: This was a double-blind, randomised, placebo-controlled, phase 3 trial that was done at 204 centres in 25 countries. Eligible patients were 18 years or older, had HER2-positive, metastatic breast cancer, had not received previous chemotherapy or biological treatment for their metastatic disease, and had an Eastern Cooperative Oncology Group performance status of 0 or 1. All study drugs were given intravenously, every 3 weeks. Patients were assigned to receive either pertuzumab or placebo at a loading dose of 840 mg, and 420 mg thereafter; plus trastuzumab at 8 mg/kg loading dose and 6 mg/kg thereafter; and docetaxel at 75 mg/m2, escalating to 100 mg/m2 if tolerated. Pertuzumab or placebo and trastuzumab were given until disease progression; docetaxel was given for six cycles, or longer at the investigators' discretion. Randomisation (1:1) was done by use of an interactive voice-response system and was stratified by geographical region (Asia, Europe, North America, or South America) and previous treatment (previous adjuvant or neoadjuvant chemotherapy vs none). The primary endpoint was independent review facility-assessed progression-free survival, which has been reported previously. Since the confirmatory overall survival analysis had also occurred before this prespecified end-of-study analysis, analyses presented here are descriptive. Overall survival analyses were based on the intention-to-treat population with crossover patients analysed in the placebo group; analyses were not adjusted for crossover to the pertuzumab group and are likely to be conservative. Safety analyses were based on treatment received; crossover patients were counted in the placebo group up to the day before first pertuzumab dose. This trial is registered with ClinicalTrials.gov, number NCT00567190. FINDINGS: Between Feb 12, 2008, and July 7, 2010, 1196 patients were assessed for eligibility, of whom 808 were enrolled and randomly assigned. 402 patients were assigned to receive docetaxel plus trastuzumab plus pertuzumab, and 406 patients were assigned to receive docetaxel plus trastuzumab plus placebo. Clinical cutoff for this analysis was Nov 23, 2018. Between July 2012 and clinical cutoff, 50 patients crossed from the placebo to the pertuzumab group. Median follow-up was 99·9 months in the pertuzumab group (IQR 92·9-106·4) and 98·7 months (90·9-105·7) in the placebo group. Median overall survival was 57·1 months (95% CI 50-72) in the pertuzumab group and 40·8 months (36-48) in the placebo group (hazard ratio 0·69, 95% CI 0·58-0·82); 8-year landmark overall survival rates were 37% (95% CI 31-42) in the pertuzumab group and 23% (19-28) in the placebo group. The most common grade 3-4 adverse event was neutropenia (200 [49%] of 408 patients in the pertuzumab group, 183 [46%] of 396 patients in the placebo group). Five (1%) of 408 patients in the pertuzumab group and six (2%) of 396 patients in the placebo group had treatment-related deaths. One new serious adverse event suggestive of congestive heart failure (pertuzumab group) and one new symptomatic left ventricular systolic dysfunction (post-crossover) occurred since the previous analysis. INTERPRETATION: Our analysis shows that the previously observed improvements in overall survival with pertuzumab, trastuzumab, and docetaxel versus placebo, trastuzumab, and docetaxel were maintained after a median of more than 8 years of follow-up. The long-term safety and cardiac safety profiles of pertuzumab, trastuzumab, and docetaxel were maintained in the overall safety population and within crossover patients. HER2-targeted therapy has changed the natural history of HER2-positive metastatic breast cancer, with the dual blockade of pertuzumab and trastuzumab, with docetaxel, demonstrating an 8-year landmark overall survival rate of 37%. FUNDING: F Hoffmann-La Roche and Genentech.

6 versus 12 months of adjuvant trastuzumab for HER2-positive early breast cancer (PERSEPHONE): 4-year disease-free survival results of a randomised phase 3 non-inferiority trial.

BACKGROUND: Adjuvant trastuzumab significantly improves outcomes for patients with HER2-positive early breast cancer. The standard treatment duration is 12 months but shorter treatment could provide similar efficacy while reducing toxicities and cost. We aimed to investigate whether 6-month adjuvant trastuzumab treatment is non-inferior to the standard 12-month treatment regarding disease-free survival. METHODS: This study is an open-label, randomised phase 3 non-inferiority trial. Patients were recruited from 152 centres in the UK. We randomly assigned patients with HER2-positive early breast cancer, aged 18 years or older, and with a clear indication for chemotherapy, by a computerised minimisation process (1:1), to receive either 6-month or 12-month trastuzumab delivered every 3 weeks intravenously (loading dose of 8 mg/kg followed by maintenance doses of 6 mg/kg) or subcutaneously (600 mg), given in combination with chemotherapy (concurrently or sequentially). The primary endpoint was disease-free survival, analysed by intention to treat, with a non-inferiority margin of 3% for 4-year disease-free survival. Safety was analysed in all patients who received trastuzumab. This trial is registered with EudraCT (number 2006-007018-39), ISRCTN (number 52968807), and ClinicalTrials.gov (number NCT00712140). FINDINGS: Between Oct 4, 2007, and July 31, 2015, 2045 patients were assigned to 12-month trastuzumab treatment and 2044 to 6-month treatment (one patient was excluded because they were double randomised). Median follow-up was 5·4 years (IQR 3·6-6·7) for both treatment groups, during which a disease-free survival event occurred in 265 (13%) of 2043 patients in the 6-month group and 247 (12%) of 2045 patients in the 12-month group. 4-year disease-free survival was 89·4% (95% CI 87·9-90·7) in the 6-month group and 89·8% (88·3-91·1) in the 12-month group (hazard ratio 1·07 [90% CI 0·93-1·24], non-inferiority p=0·011), showing non-inferiority of the 6-month treatment. 6-month trastuzumab treatment resulted in fewer patients reporting severe adverse events (373 [19%] of 1939 patients vs 459 [24%] of 1894 patients, p=0·0002) or stopping early because of cardiotoxicity (61 [3%] of 1939 patients vs 146 [8%] of 1894 patients, p<0·0001). INTERPRETATION: We have shown that 6-month trastuzumab treatment is non-inferior to 12-month treatment in patients with HER2-positive early breast cancer, with less cardiotoxicity and fewer severe adverse events. These results support consideration of reduced duration trastuzumab for women at similar risk of recurrence as to those included in the trial. FUNDING: UK National Institute for Health Research, Health Technology Assessment Programme.

Comparison of Whole-Body MRI, CT, and Bone Scintigraphy for Response Evaluation of Cancer Therapeutics in Metastatic Breast Cancer to Bone.

Background CT and bone scintigraphy have limitations in evaluating systemic anticancer therapy (SACT) response in bone metastases from metastatic breast cancer (MBC). Purpose To evaluate whether whole-body MRI enables identification of progressive disease (PD) earlier than CT and bone scintigraphy in bone-only MBC. Materials and Methods This prospective study evaluated participants with bone-only MBC between May 2016 and January 2019 (ClinicalTrials.gov identifier: NCT03266744). Participants were enrolled at initiation of first or subsequent SACT based on standard CT and bone scintigraphy imaging. Baseline whole-body MRI was performed within 2 weeks of entry; those with extraosseous disease were excluded. CT and whole-body MRI were performed every 12 weeks until definitive PD was evident with one or both modalities. In case of PD, bone scintigraphy was used to assess for bone disease progression. Radiologists independently interpreted images from CT, whole-body MRI, or bone scintigraphy and were blinded to results with the other modalities. Systematic differences in performance between modalities were analyzed by using the McNemar test. Results Forty-five participants (mean age, 60 years ± 13 [standard deviation]; all women) were evaluated. Median time on study was 36 weeks (range, 1-120 weeks). Two participants were excluded because of unequivocal evidence of liver metastases at baseline whole-body MRI, two participants were excluded because they had clinical progression before imaging showed PD, and one participant was lost to follow-up. Of the 33 participants with PD at imaging, 67% (22 participants) had PD evident at whole-body MRI only and 33% (11 participants) had PD at CT and whole-body MRI concurrently; none had PD at CT only (P < .001, McNemar test). There was only slight agreement between whole-body MRI and CT (Cohen κ, 0.15). PD at bone scintigraphy was reported in 50% of participants (13 of 26) with bone progression at CT and/or whole-body MRI (P < .001, McNemar test). Conclusion Whole-body MRI enabled identification of progressive disease before CT in most participants with bone-only metastatic breast cancer. Progressive disease at bone scintigraphy was evident in only half of participants with bone progression at whole-body MRI. © RSNA, 2020 Online supplemental material is available for this article.

The effects of hyperthermia on human hepatocellular carcinoma stem and mature cancer cells.

INTRODUCTION AND OBJECTIVES: Hepatocellular carcinoma (HCC) can recur following radiofrequency ablation and other hyperthermic treatment modalities. Cancer stem cells (CSCs) are a subpopulation of HCC cells that are difficult to eradicate and largely responsible for tumor recurrences. Thus, the principal objective of this study was to determine whether human HCC CSCs are relatively thermal-resistant compared to non-stem or mature cancer cells (MCCs). MATERIALS AND METHODS: Epithelial cell adhesion molecule (EpCAM) positive enriched CSCs and EpCAM- MCCs were derived from a human HCC cell line using fluorescence activated cell sorting. Each cell population was exposed to 65°C heat for 0-16min and survival documented at various time points. RESULTS: Cell survival curves were similar in CSC and MCCs throughout the 16min heat exposure period. Maximum killing was obtained after 12-14min of heat exposure. Cytoprotective, heat shock proteins-70 (HSP70) and -90 (HSP90) mRNA expression were not disproportionately increased in CSCs. CONCLUSIONS: These results suggest that human HCC CSCs are not more thermal resistant than MCCs and therefore, do not support the hypothesis that HCC recurrences following hyperthermic treatment reflect CSC thermal-resistance.

Adjuvant trastuzumab duration trials in HER2 positive breast cancer - what results would be practice-changing? Persephone investigator questionnaire prior to primary endpoint results.

BACKGROUND: Twelve months treatment is the current standard of care for adjuvant trastuzumab in patients with HER2 positive early breast cancer however the optimal duration is not known. Persephone is a non-inferiority randomised controlled trial comparing 6- to 12-months of trastuzumab. In this trial there will be a trade-off between a possible small decrease in disease-free survival (DFS) with 6-months and reduced cardiotoxicity and cost. METHODS: A structured questionnaire asked clinicians who had recruited patients into the Persephone trial about their prior beliefs with regards to the clinical effectiveness of trastuzumab and cardiotoxicity profile, in the comparison of 6- and 12-month durations. RESULTS: Fifty-one clinicians from 40 of the 152 Persephone sites completed the questionnaire. 30/50 responders (60%) believed that 6-months trastuzumab would give the same 4-year DFS rate as 12-months trastuzumab, with 21/50 (42%) holding this belief across all breast cancer subsets. In addition, 46/49 responders (94%) reported expecting to change their clinical practice to 6-months, with their prior beliefs (most commonly 85% 4-year DFS rate with 6-months) being greater than their lowest acceptable rate (most commonly 83% 4-year DFS rate with 6-months). Low levels of cardiotoxicity were expected with both 6 and 12-months trastuzumab, with the majority expecting lower levels with 6-months. With increasing hypothesised differences of cardiotoxicity rates between the two durations, significantly lower levels of 4-year DFS with 6-months trastuzumab were deemed acceptable (p < 0.0001). CONCLUSION: Most responders believe that 6-months trastuzumab is adequate, both overall and within each subset of breast cancer, and plan to change their clinical practice if the Persephone results support their prior belief. An individual patient meta-analysis of the duration trials would give greater precision to estimates of the differences in efficacy and toxicity, and adequate statistical power to establish a 2% level of non-inferiority for 6-months adjuvant trastuzumab.

Trastuzumab emtansine versus capecitabine plus lapatinib in patients with previously treated HER2-positive advanced breast cancer (EMILIA): a descriptive analysis of final overall survival results from a randomised, open-label, phase 3 trial.

BACKGROUND: The antibody-drug conjugate trastuzumab emtansine is indicated for the treatment of patients with HER2-positive metastatic breast cancer previously treated with trastuzumab and a taxane. Approval of this drug was based on progression-free survival and interim overall survival data from the phase 3 EMILIA study. In this report, we present a descriptive analysis of the final overall survival data from that trial. METHODS: EMILIA was a randomised, international, open-label, phase 3 study of men and women aged 18 years or older with HER2-positive unresectable, locally advanced or metastatic breast cancer previously treated with trastuzumab and a taxane. Enrolled patients were randomly assigned (1:1) via a hierarchical, dynamic randomisation scheme and an interactive voice response system to trastuzumab emtansine (3·6 mg/kg intravenously every 3 weeks) or control (capecitabine 1000 mg/m2 self-administered orally twice daily on days 1-14 on each 21-day cycle, plus lapatinib 1250 mg orally once daily on days 1-21). Randomisation was stratified by world region (USA vs western Europe vs or other), number of previous chemotherapy regimens for unresectable, locally advanced, or metastatic disease (0 or 1 vs >1), and disease involvement (visceral vs non-visceral). The coprimary efficacy endpoints were progression-free survival (per independent review committee assessment) and overall survival. Efficacy was analysed in the intention-to-treat population; safety was analysed in all patients who received at least one dose of study treatment, with patients analysed according to the treatment actually received. On May 30, 2012, the study protocol was amended to allow crossover from control to trastuzumab emtansine after the second interim overall survival analysis crossed the prespecified overall survival efficacy boundary. This study is registered with ClinicalTrials.gov, number NCT00829166. FINDINGS: Between Feb 23, 2009, and Oct 13, 2011, 991 eligible patients were enrolled and randomly assigned to either trastuzumab emtansine (n=495) or capecitabine and lapatinib (control; n=496). In this final descriptive analysis, median overall survival was longer with trastuzumab emtansine than with control (29·9 months [95% CI 26·3-34·1] vs 25·9 months [95% CI 22·7-28·3]; hazard ratio 0·75 [95% CI 0·64-0·88]). 136 (27%) of 496 patients crossed over from control to trastuzumab emtansine after the second interim overall survival analysis (median follow-up duration 24·1 months [IQR 19·5-26·1]). Of those patients originally randomly assigned to trastuzumab emtansine, 254 (51%) of 495 received capecitabine and 241 [49%] of 495 received lapatinib (separately or in combination) after study drug discontinuation. In the safety population (488 patients treated with capecitabine plus lapatinib, 490 patients treated with trastuzumab emtansine), fewer grade 3 or worse adverse events occurred with trastuzumab emtansine (233 [48%] of 490) than with capecitabine plus lapatinib control treatment (291 [60%] of 488). In the control group, the most frequently reported grade 3 or worse adverse events were diarrhoea (103 [21%] of 488 patients) followed by palmar-plantar erythrodysaesthesia syndrome (87 [18%]), and vomiting (24 [5%]). The safety profile of trastuzumab emtansine was similar to that reported previously; the most frequently reported grade 3 or worse adverse events in the trastuzumab emtansine group were thrombocytopenia (70 [14%] of 490), increased aspartate aminotransferase levels (22 [5%]), and anaemia (19 [4%]). Nine patients died from adverse events; five of these deaths were judged to be related to treatment (two in the control group [coronary artery disease and multiorgan failure] and three in the trastuzumab emtansine group [metabolic encephalopathy, neutropenic sepsis, and acute myeloid leukaemia]). INTERPRETATION: This descriptive analysis of final overall survival in the EMILIA trial shows that trastuzumab emtansine improved overall survival in patients with previously treated HER2-positive metastatic breast cancer even in the presence of crossover treatment. The safety profile was similar to that reported in previous analyses, reaffirming trastuzumab emtansine as an efficacious and tolerable treatment in this patient population. FUNDING: F Hoffmann-La Roche/Genentech.

Trastuzumab-associated cardiac events in the Persephone trial.

BACKGROUND: We report cardiac events in the Persephone trial which compares 6-12 months of adjuvant trastuzumab in women with confirmed HER2-positive, early-stage breast cancer. METHODS: Clinical cardiac events were defined as any of the following: symptoms and/or signs of congestive heart failure (CHF) and new or altered CHF medication. In addition, left ventricular ejection fraction (LVEF) was measured at baseline and then 3 monthly for 12 months. RESULTS: A total of 2500 patients, aged 22-82, were included: 1251 randomised to 12 months and 1249 to 6 months of trastuzumab treatment. A total of 93% (2335/2500) received anthracyclines, 49% of these (1136/2335) with taxanes. Cardiotoxicity delayed treatment in 6% of 12-month and 4% of 6-month patients (P=0.01), and stopped treatment early in 8% (96/1214) of 12-month and 4% (45/1216) of 6-month patients (P<0.0001). Between 7 and 12 months, more 12-month than 6-month patients had LVEFs<50% (8% vs 5%; P=0.004). LVEFs showed quadratic change over time, and 6-month patients had a more rapid recovery (P=0.02). In a landmark analysis twice as many 12-month patients, free of cardiac events at 6 months, had cardiac problems in months 7-12 (6% (66/1046) vs 3% (29/1035) of 6-month patients (P=0.0002)). Lower baseline LVEF predicted more cardiac dysfunction in both arms (reference ⩾65%: 55 to <65% OR 1.61 (95% CI 1.26-2.04); <55% OR 5.22 (3.42-7.95)) as did increasing age (reference <50: 50-59 OR 1.58 (1.17-2.12), 60-69 OR 1.91 (1.42-2.57)) 70+ OR 2.72 (1.82-4.08)) and prior use of cardiac medication (OR 8.46 (4.69-15.25)). >3 cycles of anthracycline was associated with higher risk of cardiac events only for 12-month patients (OR 1.41 (1.04-1.90)), and not for 6-month patients (OR 1.28 (0.91-1.79)). CONCLUSIONS: We demonstrate significantly fewer cardiac events from 6 months of adjuvant trastuzumab compared with that from 12 months. This cardiac signal adds importance to the question of the optimum duration of adjuvant trastuzumab treatment. If 6 months is proven to have non-inferior outcomes to 12 months treatment, these data would support 6 months as the standard of care.

Essential role of eIF5-mimic protein in animal development is linked to control of ATF4 expression.

Translational control of transcription factor ATF4 through paired upstream ORFs (uORFs) plays an important role in eukaryotic gene regulation. While it is typically induced by phosphorylation of eIF2α, ATF4 translation can be also induced by expression of a translational inhibitor protein, eIF5-mimic protein 1 (5MP1, also known as BZW2) in mammals. Here we show that the 5MP gene is maintained in eukaryotes under strong purifying selection, but is uniquely missing in two major phyla, nematoda and ascomycota. The common function of 5MP from protozoa, plants, fungi and insects is to control translation by inhibiting eIF2. The affinity of human 5MP1 to eIF2ß was measured as being equivalent to the published value of human eIF5 to eIF2ß, in agreement with effective competition of 5MP with eIF5 for the main substrate, eIF2. In the red flour beetle, Tribolium castaneum, RNA interference studies indicate that 5MP facilitates expression of GADD34, a downstream target of ATF4. Furthermore, both 5MP and ATF4 are essential for larval development. Finally, 5MP and the paired uORFs allowing ATF4 control are conserved in the entire metazoa except nematoda. Based on these findings, we discuss the phylogenetic and functional linkage between ATF4 regulation and 5MP expression in this group of eukaryotes.

Trastuzumab emtansine for HER2-positive advanced breast cancer.

BACKGROUND: Trastuzumab emtansine (T-DM1) is an antibody-drug conjugate incorporating the human epidermal growth factor receptor 2 (HER2)-targeted antitumor properties of trastuzumab with the cytotoxic activity of the microtubule-inhibitory agent DM1. The antibody and the cytotoxic agent are conjugated by means of a stable linker. METHODS: We randomly assigned patients with HER2-positive advanced breast cancer, who had previously been treated with trastuzumab and a taxane, to T-DM1 or lapatinib plus capecitabine. The primary end points were progression-free survival (as assessed by independent review), overall survival, and safety. Secondary end points included progression-free survival (investigator-assessed), the objective response rate, and the time to symptom progression. Two interim analyses of overall survival were conducted. RESULTS: Among 991 randomly assigned patients, median progression-free survival as assessed by independent review was 9.6 months with T-DM1 versus 6.4 months with lapatinib plus capecitabine (hazard ratio for progression or death from any cause, 0.65; 95% confidence interval [CI], 0.55 to 0.77; P<0.001), and median overall survival at the second interim analysis crossed the stopping boundary for efficacy (30.9 months vs. 25.1 months; hazard ratio for death from any cause, 0.68; 95% CI, 0.55 to 0.85; P<0.001). The objective response rate was higher with T-DM1 (43.6%, vs. 30.8% with lapatinib plus capecitabine; P<0.001); results for all additional secondary end points favored T-DM1. Rates of grade 3 or 4 adverse events were higher with lapatinib plus capecitabine than with T-DM1 (57% vs. 41%). The incidences of thrombocytopenia and increased serum aminotransferase levels were higher with T-DM1, whereas the incidences of diarrhea, nausea, vomiting, and palmar-plantar erythrodysesthesia were higher with lapatinib plus capecitabine. CONCLUSIONS: T-DM1 significantly prolonged progression-free and overall survival with less toxicity than lapatinib plus capecitabine in patients with HER2-positive advanced breast cancer previously treated with trastuzumab and a taxane. (Funded by F. Hoffmann-La Roche/Genentech; EMILIA ClinicalTrials.gov number, NCT00829166.).

Is undertransfusion a problem in modern clinical practice?

BACKGROUND: Significant progress has been made in reducing inappropriate transfusion of blood products. However, there is also a need to monitor for their underutilization in patients who would benefit from transfusion. This study aimed to develop a method to monitor for undertransfusion and conduct a preliminary examination of whether it is a problem in modern clinical practice. STUDY DESIGN AND METHODS: All patients with a hemoglobin (Hb) concentration below 6 g/dL or platelet (PLT) count of fewer than 10 × 10(9) /L were identified during a 1-month period in an academic medical center in the United Kingdom. Patients who were transfused within 72 hours of the low reading were excluded from further analysis. For all other patients, records were examined against predefined criteria to ascertain whether the reason for nonadministration of transfusion was justified. RESULTS: During the study period there were 63 eligible Hb readings and 130 eligible PLT counts in 93 patients. Of these, 36 patients were not transfused within 72 hours of the low reading. The majority of nonadministration (n = 28) was justified by either an additional Hb or an additional PLT count on repeat sampling being above the transfusion threshold or the transfusion being medically inappropriate. No documentation was found to indicate that any cases of nonadministration of blood were unjustified. CONCLUSION: This study did not find that patients with low Hb readings or PLT counts were inappropriately undertransfused. However, systems similar to those described in this study should be developed to monitor for inappropriate undertransfusion as well as continuing efforts to monitor for and reduce inappropriate overtransfusion.

Implementation of a clinical decision support system improves compliance with restrictive transfusion policies in hematology patients.

BACKGROUND: There is increasing evidence for restrictive red blood cell (RBC) transfusion but compliance with recommended transfusion triggers is variable. A clinical decision support system (CDSS) has been found to reduce unnecessary transfusion in some clinical settings when physicians are advised they are noncompliant with the current guidelines. The objective was to assess the impact of a CDSS for blood product ordering in patients with hematologic disease. STUDY DESIGN AND METHODS: All platelet (PLT) and RBC transfusions were identified in hematology patients in three periods: before (baseline), immediately after (CDSS1), and 7 months after implementation of CDSS for blood ordering (CDSS2). Compliance with the recommended transfusion triggers was monitored for all orders made by CDSS or non-CDSS methods during each period. RESULTS: Ninety-seven patients with a variety of hematologic diagnoses received 502 RBC and 572 PLT transfusions during the three periods with no significant difference in 1) the mean number of transfusions per patient, 2) the proportion of patients transfused, 3) posttransfusion hemoglobin (Hb), and 4) pre- and posttransfusion PLT count, although mean pretransfusion Hb decreased. The proportion of noncompliant RBC and PLT transfusion requests improved from baseline to CDSS2 (69.0% to 43.4% p ≤ 0.005 for RBCs; and 41.9% to 31.2%, p = 0.16 for PLT) when all orders were compared, although this improvement was not significant at the 5% level for PLTs. CONCLUSIONS: The introduction of CDSS for blood product ordering supported by education and physician feedback in the hematology setting had an immediate impact on improving compliance with guidelines for restrictive transfusion practice.