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Supplementary Figure S1. Distribution of HER2 expression (measured by HERmark) in all patients (left) and in 3+ IHC cohort patients (right). All patient: n=324; IHC3+: n=232.

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. Clin Cancer Res; 22(3); 560–6. ©2015 AACR.

Supplementary Data from Clinical Benefit of Lapatinib-Based Therapy in Patients with Human Epidermal Growth Factor Receptor 2–Positive Breast Tumors Coexpressing the Truncated p95HER2 Receptor

Supplementary Table S1. Multivariate Models in the IHC 3+ Subgroup

Purpose: Expression of p95HER2 has been associated with resistance to trastuzumab-based therapy in patients with metastatic breast cancer. Conversely, high levels of HER2 have been linked with increased clinical benefit from anti-HER2 therapy. In this work, we aimed to investigate whether the levels of p95HER2 and HER2 can predict response to anti-HER2 therapy in patients with breast cancer.Experimental Design: We measured p95HER2 and HER2 by VeraTag and HERmark, respectively, in primary tumors of patients enrolled in the neoadjuvant phase III study NeoALTTO and correlated these variables with pathologic complete response (pCR) and progression-free survival (PFS) following lapatinib (L), trastuzumab (T), or the combination of both agents (L+T).Results: A positive correlation between p95HER2 and HER2 levels was found in the 274 cases (60%) in which quantification of both markers was possible. High levels of these markers were predictive for pCR, especially in the hormone receptor (HR)–positive subset of patients. High HER2 expression was associated with increased pCR rate upon L+T irrespective of the HR status. To examine whether the levels of either p95HER2 or HER2 could predict for PFS in patients treated with lapatinib, trastuzumab or L+T, we fit to the PFS data in Cox models containing log2(p95HER2) or log2(HER2). Both variables correlated with longer PFS.Conclusions: Increasing HER2 protein expression correlated with increased benefit of adding lapatinib to trastuzumab. HER2 expression is a stronger predictor of pCR and PFS than p95HER2 for response to lapatinib, trastuzumab and, more significantly, L+T. Clin Cancer Res; 21(3); 569–76. ©2014 AACR.

Purpose: A subgroup of human epidermal growth factor receptor 2 (HER2)–overexpressing breast tumors coexpresses p95HER2, a truncated HER2 receptor that retains a highly functional HER2 kinase domain but lacks the extracellular domain and results in intrinsic trastuzumab resistance. We hypothesized that lapatinib, a HER2 tyrosine kinase inhibitor, would be active in these tumors. We have studied the correlation between p95HER2 expression and response to lapatinib, both in preclinical models and in the clinical setting.Experimental Design: Two different p95HER2 animal models were used for preclinical studies. Expression of p95HER2 was analyzed in HER2-overexpressing breast primary tumors from a first-line lapatinib monotherapy study (EGF20009) and a second-line lapatinib in combination with capecitabine study (EGF100151). p95HER2 expression was correlated with overall response rate (complete + partial response), clinical benefit rate (complete response + partial response + stable disease ≥24 wk), and progression-free survival using logistic regression and Cox proportional hazard models.Results: Lapatinib inhibited tumor growth and the HER2 downstream signaling of p95HER2-expressing tumors. A total of 68 and 156 tumors from studies EGF20009 and EGF100151 were evaluable, respectively, for p95HER2 detection. The percentage of p95HER2-positive patients was 20.5% in the EGF20009 study and 28.5% in the EGF100151 study. In both studies, there was no statistically significant difference in progression-free survival, clinical benefit rate, and overall response rate between p95HER2-positive and p95HER2-negative tumors.Conclusions: Lapatinib as a monotherapy or in combination with capecitabine seems to be equally effective in patients with p95HER2-positive and p95HER2-negative HER2-positive breast tumors. Clin Cancer Res; 16(9); 2688–95. ©2010 AACR.

Purpose: Lapatinib, a dual epidermal growth factor receptor (EGFR) and HER2 inhibitor, remains unproven in non–HER2-amplified metastatic breast cancer (MBC). EGF30008, a phase III trial of letrozole and lapatinib versus letrozole and placebo, demonstrated that lapatinib significantly improves outcome for postmenopausal women with HER2-amplified, but not HER2-negative, MBC. The hypothesis that low hormone receptor status is associated with benefit in this HER2-negative cohort was tested.Experimental Design: A blinded retrospective biomarker evaluation used immunohistochemistry (IHC) to semiquantify estrogen receptor (ER) and progesterone receptor (PgR) expression (n = 821/952). HER2 status was determined by IHC and confirmed by FISH (n = 326). Effects of these biomarkers on progression-free survival (PFS) were examined in patients with available tissue.Results: In HER2-negative, ER-positive MBC, median PFS was analyzed by ER and PgR expression (H-score) by quartile (Q). There was significant improvement in patients with low ER expression (Q1, H-score P = 0.01). No benefit was associated with stronger ER expression (Q2/3, H-score ≥160 and Conclusion: In postmenopausal patients with advanced hormone receptor–positive disease, weak ER expression is associated with worse outcome with letrozole treatment compared with the combination. The addition of lapatinib significantly improved PFS for this patient subgroup and augments data supporting interaction between steroid hormone and peptide hormone signaling. A prospective study validating this hypothesis is required. Clin Cancer Res; 20(3); 736–43. ©2013 AACR.

PDF - 66K, This table contains the clinical characterisitcs of patients enrolled in the EGF 30008 trial.

Supplementary Figure S1 and Supplementary Tables S1-S2. Supplementary Figure S1. Diagram of tissue block usage for CNB Development Study and Chemo-prediction Validation Study. Supplemental Table S1. Top-10 and bottom-10 Prosigna gene-correlations between paired CNBs and SRS. Supplemental Table S2. Distribution of the Prosigna subtypes within the three main pathology-based groups in 39 independent metastatic samples.

CCR Translation for This Article from Quantitative ER and PgR Assessment as Predictors of Benefit from Lapatinib in Postmenopausal Women with Hormone Receptor–Positive, HER2-Negative Metastatic Breast Cancer

BackgroundThis 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.MethodsFollowing a PROSPERO registered systematic review synthesising the three strands outlined, twenty‐eight 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.ResultsThe 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.ConclusionsWe 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. Whilst these conclusions have been drawn from wider studies aimed at reducing child maltreatment, we emphasise lessons to be drawn for SUDI prevention work with families with children at risk of significant harm.

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.

Evan Durbin was a democratic socialist, an economist and a politician. In the 1930s, his work was central to the Labour Party’s adoption of economic planning. During and after the Second World War, Durbin championed a socialist planned economy that maximized individual liberty and rejected sectional interests. He was elected as a Labour Member of Parliament in 1945 and served as a junior minister in Clement Attlee’s government. His distinctive formulation of socialism melded economics with ethics and insights drawn from psychology and psychoanalysis, underpinned by a belief in the superiority of English values and institutions. Durbin’s ethical vision and interest in affluence, voter psychology and managerialism informed Labour’s policy debates in the 1950s and ensured the continued relevance of his ideas.

La deficiencia moderada o severa de magnesio (Mg2+) lleva a anormalidades bioquímicas y manifestaciones clínicas relacionadas con el músculo esquelético, músculo cardiaco y patologías renales. El Mg2+participa en múltiples procesos homeostáticos como el metabolismo energético, la duplicación y transcripción de material genético, el transporte de sustancias a través de la membrana citoplasmática y reacciones enzimáticas. La regulación de las concentraciones de Mg2+ en el líquido extracelular y en el líquido intracelular depende de factores hormonales (insulina y hormona paratiroidea); intestinales (absorción paracelular) y renales (reabsorción en el asa de Henle); además de los depósitos de reserva en hueso y músculo. A pesar de que el Mg2+ está presente en varios alimentos, estudios en subpoblaciones costarricenses evidencian dietas con inadecuado aporte de Mg2+. La hipomagnesemia provocada por dietas insuficientes de Mg2+ contribuye a desarrollar procesos patológicos tales como calambres, arritmias e hipertensión arterial. La presente revisión pretende describir las bases de la función del Mg2+ en la fisiología humana; los mecanismos de absorción, regulación, excreción y su homeostasis, así como la importancia clínica de los efectos de su baja ingesta, la cual se vuelve cada vez más prevalente.

This volume covers aspects of sudden infant and early childhood death, ranging from issues with parental grief, to the most recent theories of brainstem neurotransmitters. It also deals with the changes that have occurred over time with the definitions of SIDS (sudden infant death syndrome), SUDI (sudden unexpected death in infancy) and SUDIC (sudden unexpected death in childhood).The text will be indispensable for SIDS researchers, SIDS organisations, paediatric pathologists, forensic pathologists, paediatricians and families, in addition to residents in training programs that involve paediatrics. It will also be of use to other physicians, lawyers and law enforcement officials who deal with these cases, and should be a useful addition to all medical examiner/forensic, paediatric and pathology departments, hospital and university libraries on a global scale. Given the marked changes that have occurred in the epidemiology and understanding of SIDS and sudden death in the very young over the past decade, a text such as this is very timely and is also urgently needed.

Summary Many factors affect child and adolescent mortality in high-income countries. These factors can be conceptualised within four domains—intrinsic (biological and psychological) factors, the physical environment, the social environment, and service delivery. The most prominent factors are socioeconomic gradients, although the mechanisms through which they exert their effects are complex, affect all four domains, and are often poorly understood. Although some contributing factors are relatively fixed—including a child's sex, age, ethnic origin, and genetics, some parental characteristics, and environmental conditions—others might be amenable to interventions that could lessen risks and help to prevent future child deaths. We give several examples of health service features that could affect child survival, along with interventions, such as changes to the physical or social environment, which could affect upstream (distal) factors.

Background\ud 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.\ud \ud Methods\ud 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.\ud \ud Results\ud 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.\ud \ud Conclusions\ud 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.

This article explores Anthony Crosland's rejection of Marxism in the early 1940s through his reading of Lucien Laurat's Marxism and Democracy (1940). In correspondence with his friend Philip Williams, Crosland commented in unusual depth on Laurat's book. Using this correspondence alongside other contemporary writing, this article argues that Laurat's ideas helped Crosland untangle his own early thoughts on the relationship between Marxism and democratic socialism and establish the limitations of Marxist analysis for contemporary conditions. These themes contributed to an interpretation of modern capitalism that became central to Crosland's post-war writing and the emergence of ‘revisionist’ socialism in Britain. Furthermore, the Left Book Club's translation of Laurat's book and continued parallels between Crosland's and Laurat's analyses in the 1950s open the possibility of greater connections between continental European and ‘revisionist’ British socialism.

This article examines the deployment of nationalization within Labour's policy-making in opposition after 1951. During this time, Labour's thinking about nationalization developed through three distinct phases that highlight the diverse objectives attached to the concept and the complex relationship between socialism and nationalization. From general consensus on the need for more nationalization in the early 1950s, policy developed by the end of the decade into a broader, but unclear, conception of ‘public ownership’ shaped by Trades Union Congress (TUC) opposition. Finally, between 1960 and 1964, a wider definition of ‘public ownership’ gained momentum within a modernizing agenda based on ‘planning’ that reframed ‘common ownership’ to make it relevant, cohesive and (at least from the party's perspective) socialist.

Purpose:\ud Many countries now have detailed investigations following sudden unexpected death in infancy (SUDI) but there is no clear evidence as to the most effective way to investigate SUDI. This systematic literature review addresses the following questions: What are the current models of practice for investigating SUDI? What is the evidence to support these investigative models? What are the key factors for effective SUDI investigation?\ud \ud Methods:\ud This was a systematic review of papers from Europe, North America, and Australasia, detailing models of SUDI investigation or the outcomes of SUDI investigations.\ud \ud Results:\ud The review includes data detailing four different models of investigation: police-led, coroner or medical examiner-led, healthcare-led or joint agency approach models. There were 18 different publications providing evidence of effectiveness of these models. All models, with the exception of police-led models, have the potential to reach best practice standards for SUDI investigation. Key factors identified for effective SUDI investigation include the need for mandatory investigation, strong leadership, integration with coronial services, and for investigations to be provided by specialist professionals.\ud \ud Conclusion:\ud Detailed SUDI investigation should lead to greater understanding of why infants die and should help prevent future deaths. The challenge is now to ensure that local SUDI investigative practices are as effective as possible.

A 36-year-old man presented with progressive thoracic deformity, a short history of headaches and visual impairment. Investigations revealed a unique case of spinal subarachnoid haemorrhage (sSAH) in a patient with spinal neuropathic osteoarthropathy. We discuss the imaging findings, major radiological differential diagnoses and discuss the possible mechanisms for sSAH.

In 1956, Martha Gellhorn spent an evening exploring the uncharted territory of London's espresso bars. Her impressions were recorded in an article on “the younger generation”: “Full of expectations and ignorance, I made the long sight-seeing trip through the Espresso-bar country of London, stared at the young natives, and came gladly home at last with many pictures in my mind but little understanding …. The youthful Espresso-ites remained hopelessly strangers, in their strange, small, chosen land; I can only report what I have seen.” Gellhorn's account was punctuated by references to the “strangeness” of her experience. The decor of the bars invoked “distant places” with “bull-fight posters, bamboo, tropical plants, an occasional shell or Mexican mask.” As she traveled through this “strange country,” the sight of a tortilla was “terrifying,” the customers' clothing was breathtakingly exotic, and their skin tones suggested amalgams such as “Chinese-Javanese-Siamese” or “Spanish-Arab-Cuban.” At times, Gellhorn heard French and Italian spoken freely among the espresso bars' young patrons.The foreign topography of youth culture described by Gellhorn was not unusual among accounts of young people in the 1950s, yet until recently this period has been characterized principally as a time of social peace and political apathy, “an age of prosperity and achievement” shaped by “consensus” and a return to normality after the disruption and sacrifices of the Second World War. Following an extended period of austerity, the welfare state and the managed economy seemed to have ensured full employment and an unprecedented standard of living, while the election of successive Conservative governments in 1951, 1955, and 1959 has been explained as the political reflection of rising personal prosperity and security.

Valproate is an important but uncommon cause of drug induced parkinsonism in the elderly. The development of symptoms after valproate onset is unpredictable, and severity of symptoms is unrelated to plasma levels. However, though the majority of cases improve after drug cessation, parkinsonian symptoms can persist and should prompt investigation into underlying degenerative parkinsonism, as valproate can unmask idiopathic Parkinson’s disease in susceptible individuals. This case describes a patient on chronic valproate therapy developing a severely disabling akinetic-rigid syndrome, only partially reversed on stopping valproate. We hypothesise that an increase in valproate dosage unmasked clinically silent Parkinson’s disease. The patient made an excellent recovery following cessation of valproate and commencement of dopaminergic therapy.