Neuroendocrine neoplasms: Consensus on a patient care pathway.

People with neuroendocrine neoplasms (NENs) face a multitude of challenges, including delayed diagnosis, low awareness of the cancer among healthcare professionals and limited access to multidisciplinary care and expert centres. We have developed the first patient care pathway for people living with NENs in England to guide disease management and help overcome these barriers. The pathway was developed in two phases. First, a pragmatic review of the literature was conducted, which was used to develop a draft patient care pathway. Second, the draft pathway was then updated following semi-structured interviews with carefully selected expert stakeholders. After each phase, the pathway was discussed among a multidisciplinary, expert advisory group (which comprised the authors and the Deputy Chief Operating Officer, West Suffolk NHS Foundation Trust), who reached a consensus on the ideal care pathway. This article presents the outputs of this research. The pathway identified key barriers to care and highlighted how these may be addressed, with many of the findings relevant to the rest of the UK and international audiences. NENs are increasing in incidence and prevalence in England, compounding pre-existing inequities in diagnosis and disease management. Effective integration of this pathway within NHS England will help achieve optimal, equitable care provision for all people with NENs, and should be feasible within the existing expert multidisciplinary teams across the country.

Momelotinib vs. ruxolitinib in myelofibrosis patient subgroups by baseline hemoglobin levels in the SIMPLIFY-1 trial.

A key hallmark of myelofibrosis is anemia, which ranges from mild to severe based on hemoglobin levels. To more clearly define outcomes with the Janus kinase (JAK) 1/JAK2/activin A receptor type 1 inhibitor momelotinib by anemia severity, we performed a descriptive post hoc exploratory analysis of the double-blind, randomized, phase 3 SIMPLIFY-1 study (NCT01969838; N = 432, JAK inhibitor naive, momelotinib vs. ruxolitinib); subgroups were defined by baseline hemoglobin: <10 (moderate/severe), ≥10 to <12 (mild), or ≥12 g/dL (nonanemic). Spleen and symptom results were generally consistent with those previously reported for the intent-to-treat population. In anemic subgroups, momelotinib was associated with higher rates of transfusion independence and reduced/stable transfusion intensity vs. ruxolitinib. No new or unexpected safety signals were identified. Overall, momelotinib provides spleen, symptom, and anemia benefits to JAK inhibitor-naive patients with myelofibrosis regardless of baseline hemoglobin level, and greater anemia-related benefits vs. ruxolitinib in patients with hemoglobin <12 g/dL.

Anemia-related response end points in myelofibrosis clinical trials: current trends and need for renewed consensus.

JAK inhibitors are the current standard of care in myelofibrosis, but many do not address and may worsen anemia; thus, anemia-related responses have traditionally been overlooked as efficacy end points in pivotal clinical trials, leading to a lack of consistency and analytic detail in their reporting. Here we apply our experiences in the phase III trials of momelotinib, a JAK1/JAK2/ACVR1 inhibitor and the first therapy indicated by the US FDA for myelofibrosis patients with anemia, to highlight how application of different criteria impacts the anemia-related benefits reported for any potential treatment in myelofibrosis. We advocate for a convention of a new expert consensus panel to bring consistency and transparency to the definition of anemia-related response in myelofibrosis.

What is this Perspective about? Anemia (too few healthy red blood cells) is common in patients with myelofibrosis. While it is becoming more common to measure the anemia benefits associated with potential treatments for myelofibrosis in clinical trials, different definitions of anemia benefit are available. This Perspective reviews these definitions, the differences between them, and why consistency and clarity in measuring anemia benefit matter. The definitions used in clinical trials of momelotinib, a treatment for patients with myelofibrosis and anemia, are also explained to show how the anemia benefit observed in these trials could have changed if different definitions were used. What does this Perspective show? Definitions of anemia benefit may include the number of red blood cell transfusions a patient receives, the amount of hemoglobin (a red blood cell protein) in their blood, or a combination thereof. Considerations such as timing, the types of patients included, and other factors are not consistent across definitions and not always clearly reported. Results when different definitions of anemia benefit were followed in the momelotinib clinical trials show that the amount of benefit observed with treatments changes depending on which definition is used. What conclusions can be drawn from this Perspective? More consistency and clarity in the definitions of anemia benefit in myelofibrosis clinical trials are needed, suggesting that a new panel of experts should come together to discuss this topic.

Activating Inducible T-cell Costimulator Yields Antitumor Activity Alone and in Combination with Anti-PD-1 Checkpoint Blockade.

In recent years, there has been considerable interest in mAb-based induction of costimulatory receptor signaling as an approach to combat cancer. However, promising nonclinical data have yet to translate to a meaningful clinical benefit. Inducible T-cell costimulator (ICOS) is a costimulatory receptor important for immune responses. Using a novel clinical-stage anti-ICOS immunoglobulin G4 mAb (feladilimab), which induces but does not deplete ICOS+ T cells and their rodent analogs, we provide an end-to-end evaluation of the antitumor potential of antibody-mediated ICOS costimulation alone and in combination with programmed cell death protein 1 (PD-1) blockade. We demonstrate, consistently, that ICOS is expressed in a range of cancers, and its induction can stimulate growth of antitumor reactive T cells. Furthermore, feladilimab, alone and with a PD-1 inhibitor, induced antitumor activity in mouse and humanized tumor models. In addition to nonclinical evaluation, we present three patient case studies from a first-time-in-human, phase I, open-label, dose-escalation and dose-expansion clinical trial (INDUCE-1; ClinicalTrials.gov: NCT02723955), evaluating feladilimab alone and in combination with pembrolizumab in patients with advanced solid tumors. Preliminary data showing clinical benefit in patients with cancer treated with feladilimab alone or in combination with pembrolizumab was reported previously; with example cases described here. Additional work is needed to further validate the translation to the clinic, which includes identifying select patient populations that will benefit from this therapeutic approach, and randomized data with survival endpoints to illustrate its potential, similar to that shown with CTLA-4 and PD-1 blocking antibodies. Significance: Stimulation of the T-cell activation marker ICOS with the anti-ICOS agonist mAb feladilimab, alone and in combination with PD-1 inhibition, induces antitumor activity across nonclinical models as well as select patients with advanced solid tumors.

Adolescence as the Context for Understanding Young Mothers' Engagement with Health Promotion: A Phenomenological Exploration.

BACKGROUND: The current social construction of young mothers is generally negative, pointing to a lack of engagement with universal services and poor outcomes for their infants and children. However, qualitative studies offer an alternative, more positive construct of young motherhood. Understanding the context of young motherhood can improve the relevance and efficacy of health promotion directed to this group of high-risk mothers. AIM: To explore the lived experience of young women transitioning to motherhood to better understand their experiences and perspective; and what influences their engagement with health promotion aimed to support safer parenting practices and whether their behaviour changes over time with exposure to parenting health promotion. METHOD: Longitudinal Interpretative Phenomenological Analysis (IPA) was used with five first-time mothers identified with characteristics known to influence poorer outcomes for infants and children such as low educational achievement and economic disadvantage. Participants aged 16 to 19 years were recruited antenatally. Serial in-depth interviews were conducted at three time points during the ante- and post-natal periods. Interviews were transcribed and data were analysed inductively following the prescribed method of double hermeneutic analysis for IPA. FINDING: Three themes were identified from the full study: Transition, Information, and Fractured application; the focus of this paper is Transition. Transition revealed that becoming mothers impacted key adolescent developmental tasks; their identity and relationships were significantly affected, both positively and negatively and adolescent brain development influenced behaviour and decision making capability. Adolescence influenced how these young mothers engaged with and interpreted parenting health promotion messages. CONCLUSIONS: Young mothers in this study operate within the context of adolescence. Adolescence impacts participants' decision making activity and early parenting behaviours which informs the debate on why young mothers may fail to reduce risks for their infants. This insight can contribute to the development of more effective health promotion/educational strategies, and support professionals to better engage with this high-risk group to improve early parenting behaviour and subsequently improve outcomes for their infants and children.

Second Primary Malignancies in Patients with a Neuroendocrine Neoplasm in England.

INTRODUCTION: Patients with neuroendocrine neoplasms (NENs) may often develop other malignancies. This study aimed to identify the frequency at which these second malignancies occurred in England. METHODS: Data were extracted from the National Cancer Registration and Analysis Service (NCRAS) on all patients diagnosed with a NEN at one of eight NEN site groups between 2012 and 2018: appendix, caecum, colon, lung, pancreas, rectum, small intestine, and stomach. WHO International Classification of Disease Edition-10 (ICD-10) codes were used to identify patients who had been diagnosed with an additional non-NEN cancer. Standardized incidence ratios (SIRs) for tumours diagnosed after the index NEN were produced for each non-NEN cancer type by sex and site. RESULTS: A total of 20,579 patients were included in the study. The most commonly occurring non-NEN cancers after NEN diagnosis were the prostate (20%), lung (20%), and breast (15%). Statistically significant SIRs were observed for non-NEN cancer of the lung (SIR = 1.85, 95% CI: 1.55-2.22), colon (SIR = 1.78, 95% CI: 1.40-2.27), prostate (SIR = 1.56, 95% CI: 1.31-1.86), kidney (SIR = 3.53, 95% CI: 2.72-4.59), and thyroid (SIR = 6.31, 95% CI: 4.26-9.33). When stratified by sex, statistically significant SIRs remained for the lung, renal, colon, and thyroid tumours. Additionally, females had a statistically significant SIR for stomach cancer (2.65, 95% CI: 1.26-5.57) and bladder cancer (SIR = 2.61, 95% CI: 1.36-5.02). CONCLUSION: This study found that patients with a NEN experienced a metachronous tumour of the lung, prostate, kidney, colon, and thyroid at a higher rate than the general population of England. Surveillance and engagement in existing screening programmes are required to enable earlier diagnosis of second non-NEN tumours in these patients.

A Phase I, First-in-Human Study of GSK2849330, an Anti-HER3 Monoclonal Antibody, in HER3-Expressing Solid Tumors.

BACKGROUND: GSK2849330, an anti-HER3 monoclonal antibody that blocks HER3/Neuregulin 1 (NRG1) signaling in cancer cells, is engineered for enhanced antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity. This phase I, first-in-human, open-label study assessed the safety, pharmacokinetics (PK), pharmacodynamics, and preliminary activity of GSK2849330 in patients with HER3-expressing advanced solid tumors. PATIENTS AND METHODS: Patients with various tumor types were prospectively selected for HER3 expression by immunohistochemistry; a subset was also screened for NRG1 mRNA expression. In the dose-escalation phase, patients received GSK2849330 1.4-30 mg/kg every 2 weeks, or 3 mg/kg or 30 mg/kg weekly, intravenously (IV). In the dose-expansion phase, patients received 30 mg/kg GSK2849330 IV weekly. RESULTS: Twenty-nine patients with HER3-expressing cancers, of whom two expressed NRG1, received GSK2849330 (dose escalation: n = 18, dose expansion: n = 11). GSK2849330 was well tolerated. No dose-limiting toxicities were observed. The highest dose, of 30 mg/kg weekly, expected to provide full target engagement, was selected for dose expansion. Treatment-emergent adverse events (AEs) were mostly grade 1 or 2. The most common AEs were diarrhea (66%), fatigue (62%), and decreased appetite (31%). Dose-proportional plasma exposures were achieved, with evidence of HER3 inhibition in paired tissue biopsies. Of 29 patients, only 1 confirmed partial response, lasting 19 months, was noted in a patient with CD74-NRG1-rearranged non-small cell lung cancer (NSCLC). CONCLUSION: GSK2849330 demonstrated a favorable safety profile, dose-proportional PK, and evidence of target engagement, but limited antitumor activity in HER3-expressing cancers. The exceptional response seen in a patient with CD74-NRG1-rearranged NSCLC suggests further exploration in NRG1-fusion-positive cancers. IMPLICATIONS FOR PRACTICE: This first-in-human study confirms that GSK2849330 is well tolerated. Importantly, across a variety of HER3-expressing advanced tumors, prospective selection by HER3/NRG1 expression alone was insufficient to identify patients who could benefit from treatment with this antibody-dependent cell-mediated cytotoxicity- and complement-dependent cytotoxicity-enhanced anti-HER3 antibody. The only confirmed durable response achieved was in a patient with CD74-NRG1-rearranged lung cancer. This highlights the potential utility of screening for NRG1 fusions prospectively across tumor types to enrich potential responders to anti-HER3 agents in ongoing trials.

Improving engagement with services to prevent Sudden Unexpected Death in Infancy (SUDI) in families with children at risk of significant harm: A systematic review of evidence.

This paper reports part of a wider systematic review commissioned by the English National Safeguarding Panel on Sudden Unexpected Death in Infancy (SUDI). The wider review covered three areas: interventions to improve safer sleep practices in high-risk families, interventions to improve engagement with services and decision making by parents at high risk of SUDI about infant sleep environments. Here, we report the qualitative and quantitative studies reviewed under the engagement strand. Parental engagement is understood to be a multidimensional task for health and social care professionals comprising attitudinal, relational and behavioural components. Following a PROSPERO registered systematic review synthesizing the three strands outlined, 28 papers were found to be relevant in the review of interventions to improve engagement with services in families with children at risk of significant harm through abuse or neglect. No studies were found that specifically focused on engagement of families at high risk for SUDI, so these wider engagement studies were included. The different types of intervention reported in the included studies are described under two broad themes: Enablers (including parental motivation and working with families) and Barriers. Given the focus in the studies on interventions that support parental engagement, the Enablers theme is more extensive than the Barriers reported although all studies noted well-understood barriers. The evidence underpinning these interventions and approaches are reviewed in this paper. We conclude that effective engagement is facilitated by experienced professionals given time to develop supportive non-judgemental relationships with families in their homes, working long-term, linking with communities and other services. While these conclusions have been drawn from wider studies aimed at reducing child maltreatment, we emphasize lessons to be drawn for SUDI prevention work with families with children at risk of significant harm.

Decision-making for the infant sleep environment among families with children considered to be at risk of sudden unexpected death in infancy: a systematic review and qualitative metasynthesis.

Background: Advice to families to sleep infants on their backs, avoid smoke exposure, reduce excess bedcovering and avoid specific risks associated with cosleeping has greatly reduced sudden unexpected death in infancy (SUDI) rates worldwide. The fall in rates has not been equal across all groups, and this advice has been less effective for more socially deprived families. Understanding decision-making processes of families with infants at risk would support the development of more effective interventions. Aim: To synthesise the qualitative evidence on parental decision-making for the infant sleep environment among families with children considered to be at increased risk of SUDI. Methods: This study was one of three related reviews of the literature for the Child Safeguarding Practice Review Panel's National Review in England into SUDI in families where the children are considered at risk of harm. A systematic search of eight online databases was carried out in December 2019. Metasynthesis was conducted, with themes extracted from each paper, starting with the earliest publication first. Results: The wider review returned 3367 papers, with 16 papers (across 13 studies) specifically referring to parental decision-making. Six overall themes were identified from the synthesis: (1) knowledge as different from action; (2) external advice must be credible; (3) comfort, convenience and disruption to the routine; (4) plausibility and mechanisms of protection; (5) meanings of safety and risk mitigation using alternative strategies; and (6) parents' own expertise, experience and instincts. Conclusion: Interventions that are intended to improve the uptake of safer sleep advice in families with infants at risk of sleep-related SUDI need to be based on credible advice with mechanisms of protection that are understandable, consistent with other sources, widened to all carers of the infant and fit within the complex practice of caring for infants.

Interventions to Improve Safer Sleep Practices in Families With Children Considered to Be at Increased Risk for Sudden Unexpected Death in Infancy: A Systematic Review.

Background: Advice to families to follow infant care practices known to reduce the risks of Sudden Unexpected Death in Infancy (SUDI) has led to a reduction in deaths across the world. This reduction has slowed in the last decade with most deaths now occurring in families experiencing social and economic deprivation. A systematic review of the literature was commissioned by the National Child Safeguarding Practice Review Panel in England. The review covered three areas: interventions to improve engagement with support services, parental decision-making for the infant sleep environment, and interventions to improve safer sleep practices in families with infants considered to be at risk of SUDI. Aim: To describe the safer sleep interventions tested with families with infants at risk of SUDI and investigate what this literature can tell us about what works to reduce risk and embed safer sleep practices in this group. Methods: Eight online databases were systematically searched in December 2019. Intervention studies that targeted families with infants (0-1 year) at increased risk of SUDI were included. Studies were limited to those from Western Europe, North America or Australasia, published in the last 15 years. The Quality Assessment Tool for Studies with Diverse Designs was applied to assess quality. Data from included studies were extracted for narrative synthesis, including mode of delivery using Michie et al.'s Mode of Delivery Taxonomy. Results: The wider review returned 3,367 papers, with 23 intervention papers. Five types of intervention were identified: (1) infant sleep space and safer sleep education programs, (2) intensive or targeted home visiting services, (3) peer educators/ambassadors, (4) health education/raising awareness interventions, (5) targeted health education messages using digital media. Conclusion: Influencing behavior in families with infants at risk of SUDI has traditionally focused on "getting messages across," with interventions predominantly using education and awareness raising mechanisms. This review found evidence of interventions moving from "information giving" to "information exchange" models using personalized, longer term relationship-building models. This shift may represent an improvement in how safer sleep advice is implemented in families with infants at risk, but more robust evidence of effectiveness is required. Systematic Review Registration: https://assets.publishing.service.gov.uk/government/uploads/system/uploads/attachment_data/file/901091/DfE_Death_in_infancy_review.pdf, identifier: CRD42020165302.

Phase I dose-escalation trial of the oral AKT inhibitor uprosertib in combination with the oral MEK1/MEK2 inhibitor trametinib in patients with solid tumors.

PURPOSE: This study aimed to determine the safety, tolerability, and recommended phase II doses of trametinib plus uprosertib (GSK2141795) in patients with solid tumors likely to be sensitive to MEK and/or AKT inhibition. METHODS: This was a phase I, open-label, dose-escalation, and dose-expansion study in patients with triple-negative breast cancer or BRAF-wild type advanced melanoma. The primary outcome of the expansion study was investigator-assessed response. Among 126 enrolled patients, 63 received continuous oral daily dosing of trametinib and uprosertib, 29 received various alternative dosing schedules, and 34 were enrolled into expansion cohorts. Doses tested in the expansion cohort were trametinib 1.5 mg once daily (QD) + uprosertib 50 mg QD. RESULTS: Adverse events (AEs) were consistent with those reported in monotherapy studies but occurred at lower doses and with greater severity. Diarrhea was the most common dose-limiting toxicity; diarrhea and rash were particularly difficult to tolerate. Overall, 59% and 6% of patients reported AEs with a maximum severity of grade 3 and 4, respectively. Poor tolerability prevented adequate delivery of uprosertib with trametinib at a concentration predicted to have clinical activity. The study was terminated early based on futility in the continuous-dosing expansion cohorts and a lack of pharmacological or therapeutic advantage with intermittent dosing. The objective response rate was < 5% (1 complete response, 5 partial responses). CONCLUSIONS: Continuous and intermittent dosing of trametinib in combination with uprosertib was not tolerated, and minimal clinical activity was observed in all schedules tested.

The benefit of evolving multidisciplinary care in ALS: a diagnostic cohort survival comparison.

BACKGROUND: Care for people with amyotrophic lateral sclerosis (ALS) has altered at King's College Hospital over the last 20 years. The clinic has been a multidisciplinary, specialist, tertiary referral centre since 1995 with a large team with integrated palliative and respiratory care since 2006. We hypothesised that these changes would improve survival. METHODS: In this retrospective observational study, patients diagnosed with El Escorial definite, probable and possible ALS between 1995-1998 and 2008-2011 were followed up. The primary outcome measure was a chi-square test for the proportion of each cohort surviving. Kaplan-Meier survival analysis and Cox multivariate regression were secondary analyses. RESULTS: There was low reporting of some interventions. Five hundred and forty-seven people were included. Survival between the cohorts was significantly different (p = 0.022) with a higher proportion surviving during 2008-2011. Survival time was 21.6 (95% CI 19.2-24.0) months in the 2008-2011 cohort compared to 19.2 years (15.6-21.6) in the 1995-1998 cohort (log rank p = 0.018). Four hundred and ninety-three cases were included in the Cox regression. Diagnostic cohort was a significant predictor variable (HR 0.79 (0.64-0.97) p = 0.023). CONCLUSIONS: These results support the hypothesis that integrated specialist clinics with multidisciplinary input improve survival in ALS.

Impact of serum HER2, TIMP-1, and CAIX on outcome for HER2+ metastatic breast cancer patients: CCTG MA.31 (lapatinib vs. trastuzumab).

BACKGROUND: The lapatinib-taxane combination led to shorter PFS than trastuzumab-taxane in HER2+ metastatic breast cancer. We investigated the prognostic and predictive effects of pretreatment serum HER2, CAIX, and TIMP-1. METHODS: MA.31 accrued 652 patients; 537 (82%) were centrally confirmed HER2+. Biomarkers were categorized for univariate and multivariable predictive investigations with a median cut-point, ULN cut-points (15 ng/ml for HER2; 506 pg/ml for CAIX; 454 pg/ml for TIMP-1), and custom cut-points (30 and 100 ng/ml for HER2). Stratified step-wise forward Cox multivariable analysis examined continuous and categorical effects of biomarkers on PFS in the ITT and central HER2+ populations; central HER2+ biomarker results are shown. RESULTS: Serum was banked for 472 (72%) of 652 patients. Higher serum HER2 (>median; >15; >30; or >100 ng/ml; p = 0.05-0.002); higher CAIX (>median; >506 pg/ml; p = 0.02; p = 0.001); and higher TIMP-1 (> median; > 454 pg/ml; p = 0.001; p = 0.02) had shorter univariate PFS. In multivariable analysis, higher continuous TIMP-1 was associated with significantly shorter PFS: HR = 1.001 (95% CI = 1.00-01.002; p = 0.004). Continuous serum HER2 and CAIX were not significantly associated with PFS. HER2 of 15 ng/ml or higher had shorter PFS (p = 0.02); higher categorical CAIX had shorter PFS (p = 0.01-0.08). Interaction terms of HER2, CAIX, and TIMP-1 with treatment were not significant; the predictive test power was low. CONCLUSIONS: Higher levels of serum TIMP-1, CAIX, and HER2 were significant prognostic biomarkers of shorter PFS. We found no significant interaction between serum biomarkers and response to lapatinib versus trastuzumab. Evaluation of TIMP-1 and CAIX-targeted therapy in addition to HER2-targeted therapy appears warranted in patients with elevated serum levels of these biomarkers.

HER2 Status in Advanced or Metastatic Gastric, Esophageal, or Gastroesophageal Adenocarcinoma for Entry to the TRIO-013/LOGiC Trial of Lapatinib.

HER2/ERBB2 status is used to select patients for HER2-targeted therapy. HER2/ERBB2 amplification/overexpression of upper gastrointestinal (UGI) adenocarcinomas was determined locally or in two central laboratories to select patients for the TRIO-013/LOGiC trial of chemotherapy with or without lapatinib. Patients selected locally had central laboratory confirmation of HER2 amplification for inclusion in the primary efficacy population. HER2 was assessed with PathVysion or IQ PharmDx FISH and HercepTest immunohistochemistry assays. Associations with outcomes were retrospectively evaluated. Overall, HER2 status was determined in UGI cancers from 4,674 patients in a central laboratory for eligibility (1,995 cases) and for confirmation of local HER2 results (333 cases). Of 1,995 adenocarcinomas screened centrally, 322 (16.1%) had HER2-amplified disease with 29 (1.5%) showing HER2 genomic heterogeneity. Men and older patients had higher rates of amplification. Of 545 patients accrued to the trial (gastric, 87.3%; GEJ, 8.3% and esophageal cancer, 4.4%), 487 patients (89%) were centrally confirmed as having HER2-amplified disease. Concordance between central and local HER2 testing was 83%. Concordance between PathVysion and IQ PharmDx FISH assays was 99% and FISH in the two central laboratories was 95%. Lapatinib-treated Asian participants and those less than 60 years had significant improvement in progression-free survival (PFS), particularly among those whose cancers had 5.01-10.0 and >10.0-fold amplification of HER2 In conclusion, HER2 is commonly amplified in UGI adenocarcinomas with amplification highly correlated to overexpression, and HER2 amplification levels correlated with PFS. While HER2 genomic heterogeneity occurs, its prevalence is low. Mol Cancer Ther; 16(1); 228-38. ©2016 AACR.

Unintentional asphyxia, SIDS, and medically explained deaths: a descriptive study of outcomes of child death review (CDR) investigations following sudden unexpected death in infancy.

BACKGROUND: A comprehensive child death review (CDR) program was introduced in England and Wales in 2008, but as yet data have only been analyzed at a local level, limiting the learning from deaths. The aim of this study is to describe the profile of causes and risk factors for sudden unexpected death in infancy (SUDI) as determined by the new CDR program. METHODS: This was a descriptive outcome study using data from child death overview panel Form C for SUDI cases dying during 2010-2012 in the West Midlands region of England. The main outcome measures were: cause of death, risk factors and potential preventability of death, and determination of deaths probably due to unintentional asphyxia. RESULTS: Data were obtained for 65/70 (93 %) SUDI cases. 20/65 (31 %) deaths were initially categorized as due to medical causes; 21/65 (32 %) as SIDS; and 24/65 (37 %) as undetermined. Reanalysis suggested that 2/21 SIDS and 7/24 undetermined deaths were probably due to unintentional asphyxia, with 6 of these involving co-sleeping and excessive parental alcohol consumption. Deaths classified as "undetermined" had significantly higher total family and environmental risk factor scores (mean 2.6, 95 % CI 2.0-3.3) compared to those classified as SIDS (mean 1.6, 95 % CI 1.2-1.9), or medical causes for death (mean 1.1, 95 % CI 0.8-1.3). 9/20 (47 %) of medical deaths, 19/21 (90 %) SIDS, and 23/24 (96 %) undetermined deaths were considered to be potentially preventable. There were inadequacies in medical provision identified in 5/20 (25 %) of medically explained deaths. CONCLUSIONS: The CDR program results in detailed information about risk factors for SUDI cases but failed to recognize deaths probably due to unintentional asphyxia. The misclassification of probable unintentional asphyxial deaths and SIDS as "undetermined deaths" is likely to limit learning from these deaths and inhibit prevention strategies. Many SUDI occurred in families with mental illness, substance misuse and chaotic lifestyles and most in unsafe sleep environments. This knowledge could be used to better target safe sleep advice for vulnerable families and prevent SUDI in the future.

Prognostic Value of Intrinsic Subtypes in Hormone Receptor-Positive Metastatic Breast Cancer Treated With Letrozole With or Without Lapatinib.

IMPORTANCE: The value of the intrinsic subtypes of breast cancer (luminal A, luminal B, human epidermal growth factor receptor 2 [currently known as ERBB2, but referred to as HER2 in this study]-enriched, and basal-like) in the metastatic setting is currently unknown. OBJECTIVE: To evaluate the association of the intrinsic subtypes of breast cancer with outcome and/or benefit in hormone receptor (HR)-positive metastatic breast cancer. DESIGN, SETTING, AND PARTICIPANTS: Unplanned retrospective analysis of 821 tumor samples (85.7% primary and 14.3% metastatic) from the EGF30008 phase 3 clinical trial (NCT00073528), in which postmenopausal women with HR-positive invasive breast cancer and no prior therapy for advanced or metastatic disease were randomized to letrozole with or without lapatinib, an epidermal growth factor receptor (EGFR)/HER2 tyrosine kinase inhibitor. Tumor samples were classified into each subtype using the research-based PAM50 classifier. Prior neoadjuvant/adjuvant antiestrogen therapy was allowed. Patients with extensive symptomatic visceral disease were excluded. Treatment effects were evaluated using interaction tests. MAIN OUTCOMES AND MEASURES: Primary and secondary end points were progression-free survival and overall survival. RESULTS: The median (range) age was 62 (31-94) years. Intrinsic subtype was the strongest prognostic factor independently associated with progression-free survival and overall survival in all patients, and in patients with HER2-negative (n = 644) or HER2-positive (n = 157) diseases. Median progression-free survival differed across the intrinsic subtypes of clinically HER2-negative disease: luminal A (16.9 [95% CI, 14.1-19.9] months), luminal B (11.0 [95% CI, 9.6-13.6] months), HER2-enriched (4.7 [95% CI, 2.7-10.8] months), and basal-like (4.1 [95% CI, 2.5-13.8] months). Median OS also differed across the intrinsic subtypes: luminal A (45 [95% CI, 41-not applicable {NA}] months), luminal B (37 [95% CI, 31-42] months), HER2-enriched (16 [95% CI, 10-NA] months), and basal-like (23 [95% CI, 12-NA] months). Patients with HER2-negative/HER2-enriched disease benefited from lapatinib therapy (median PFS, 6.49 vs 2.60 months; progression-free survival hazard ratio, 0.238 [95% CI, 0.066-0.863]; interaction P = .02). CONCLUSIONS AND RELEVANCE: This is the first study to reveal an association between intrinsic subtype and outcome in first-line HR-positive metastatic breast cancer. Patients with HR-positive/HER2-negative disease with a HER2-enriched profile may benefit from lapatinib in combination with endocrine therapy. The clinical value of intrinsic subtyping in hormone receptor-positive metastatic breast cancer warrants further investigation, but patients with luminal A/HER2-negative metastatic breast cancer might be good candidates for letrozole monotherapy in the first-line setting regardless of visceral disease and number of metastases.

Legal and ethical issues in neonatal nursing: a case study.

Neonatal nurses regularly face complex legal and ethical dilemmas. This article discusses the hypothetical case of Jack, a two-day-old infant diagnosed with trisomy 13 (syndrome), a life-limiting condition. Jack's prognosis is poor, and he is not expected to live past two weeks of age. The legal and ethical perspectives of withholding life-sustaining treatment in infants and children will be explored through the application of ethical frameworks, as well as statute and case law relevant to children and adolescent nursing. The article also discusses the neonatal nurse's role, with reference to local and national guidelines.

Serum Human Epidermal Growth Factor 2 Extracellular Domain as a Predictive Biomarker for Lapatinib Treatment Efficacy in Patients With Advanced Breast Cancer.

PURPOSE: We examined the prognostic and predictive value of serum human epidermal growth factor 2 (HER2) extracellular domain (sHER2) in patients with advanced breast cancer treated with lapatinib using data from three randomized trials. PATIENTS AND METHODS: We analyzed sHER2 and tissue HER2 (tHER2) data from 1,902 patients (84%) who were randomly assigned to receive lapatinib or control in the trials EGF30001, EGF30008, and EGF100151. Cox regression analyses were performed to correlate both biomarkers with progression-free survival (PFS) and overall survival (OS). RESULTS: Median sHER2 levels were 25.1 and 10.1 ng/mL in tHER2-amplified (tHER-positive) and nonamplified (tHER-negative) populations, respectively (r = 0.42 for sHER2-tHER2 correlation). Lapatinib had significant PFS benefit over control (hazard ratio [HR], 0.855; P = .004), but not OS (HR, 0.941; P = .33). Lapatinib PFS benefit is independently predicted by higher sHER2 values (HR per 10-ng/mL increase in sHER2: lapatinib-containing therapies, 1.009 v nonlapatinib-containing therapies, 1.044; P(interaction) < .001) and by positive tHER2 (HR [lapatinib v nonlapatinib]: tHER2 positive, 0.638 v tHER2 negative, 0.940; P(interaction) = .001). Within the tHER2-positive subpopulation (n = 515), higher sHER2 values still independently predicted lapatinib PFS benefit (HR per 10-ng/mL increase in sHER2: lapatinib-containing therapies, 1.017 v nonlapatinib-containing therapies, 1.041; P(interaction) = .008). In control arms (n = 936), higher sHER2 was associated with worse prognosis in multivariable analyses (PFS HR per 10 ng/mL: PFS, 1.024; P < .001; and OS, 1.018; P < .001). CONCLUSION: Higher sHER2 predicts greater PFS benefit with lapatinib independent of tHER2 status. High sHER2 is also independently prognostic for worse survival in patients who received nonlapatinib-containing therapies. The predictive role of sHER2 for other anti-HER2 agents requires further research.

Prediction of Response to Neoadjuvant Chemotherapy Using Core Needle Biopsy Samples with the Prosigna Assay.

PURPOSE: Most hormone receptor (HR)(+)/HER2(-) breast cancer patients respond unfavorably to neoadjuvant chemotherapy (NAC); however, genomic tests may identify those patients who are likely to benefit. Using the Prosigna assay, we first evaluated the technical performance of core needle biopsy (CNB) tissues. We then determined whether Prosigna risk of relapse (ROR) score and intrinsic subtype predicted response to NAC in HR(+)/HER2(-) patients using CNB samples. EXPERIMENTAL DESIGN: Using the NanoString's nCounter Dx analysis system and a development tissue sample set, we established tissue requirements and assay output variance. We then evaluated the concordance in subtype and correlation in ROR between CNBs and corresponding surgical resection specimens (SRS) in a second independent sample set. Finally, we analyzed 180 independent CNB samples from HR(+)/HER2(-) patients who were treated with NAC and correlated ROR and intrinsic subtype with pathologic response. RESULTS: Intra- and interbiopsy variabilities were 2.2 and 6.8 ROR units, respectively. Subtype concordance within multiple CNBs was high for the 4- and 3-subtype classifications (k = 0.885 and 0.889, respectively). Correlation in Prosigna ROR score observed between paired CNBs and SRS was high (r ≥ 0.90), and subtype concordance was also high for the 4- and 3-subtype classifications (kappa = 0.81 and 0.91, respectively). Prosigna results obtained from the HR(+)/HER2(-) patient samples showed that both ROR (P = 0.047) and intrinsic subtype (OR LumA vs. non-LumA = 0.341, P = 0.037) were significant predictors of response to NAC. CONCLUSIONS: Prosigna ROR and intrinsic subtype are readily obtained from CNB samples in normal practice and reliably predict response to NAC in HR(+)/HER2(-) patients.

Postoperative Adjuvant Lapatinib and Concurrent Chemoradiotherapy Followed by Maintenance Lapatinib Monotherapy in High-Risk Patients With Resected Squamous Cell Carcinoma of the Head and Neck: A Phase III, Randomized, Double-Blind, Placebo-Controlled Study.

PURPOSE: This multicenter phase III study evaluated the efficacy and safety of lapatinib, an epidermal growth factor receptor/ErbB2 inhibitor, administered concomitantly with chemoradiotherapy and as maintenance monotherapy in patients with high-risk surgically treated squamous cell carcinoma of the head and neck (SCCHN). PATIENTS AND METHODS: Patients with resected stage II to IVA SCCHN, with a surgical margin ≤ 5 mm and/or extracapsular extension, were randomly assigned to chemoradiotherapy (66 Gy total radiation dose and cisplatin 100 mg/m(2) per day administered on days 1, 22, and 43) plus placebo or lapatinib (1,500 mg per day) before and during chemoradiotherapy, followed by 12 months of maintenance monotherapy. RESULTS: Six hundred eighty-eight patients were enrolled (lapatinib, n = 346; placebo, n = 342). With a median follow-up time of 35.3 months, the study ended early because of the apparent plateauing of disease-free survival (DFS) events. Median DFS assessed by an independent review committee was 53.6 months and not reached for lapatinib and placebo, respectively (hazard ratio, 1.10; 95% CI, 0.85 to 1.43). Investigator-assessed results confirmed the independent review committee assessment. No significant differences in DFS by human papillomavirus status or overall survival were observed between treatment arms. Similar numbers of patients in both treatment arms experienced adverse events (AEs), with more patients in the lapatinib arm than the placebo arm experiencing serious AEs (48% v 40%, respectively). The most commonly observed treatment-related AEs were diarrhea and rash, both predominantly in the lapatinib arm. CONCLUSION: Addition of lapatinib to chemoradiotherapy and its use as long-term maintenance therapy does not offer any efficacy benefits and had additional toxicity compared with placebo in patients with surgically treated high-risk SCCHN.