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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.

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.

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.

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.

Background In 2005 Cairns et al. published a paper (Int J Paediatr Dent 2005; 15: 310–318) examining the role of the general dental practitioner (GDP) in child protection (CP) in Scotland. This involved a questionnaire sent out to Scottish GDPs in 2003. Subsequently in 2006 all UK dental practices were sent Child protection and the dental team, a manual detailing roles and responsibilities with regard to CP. During this time the profile of CP within dentistry increased. There has been no published research since 2006 investigating whether the gap between the proportion of GDPs who suspect child abuse/neglect in their patients and those who refer cases has changed. Aim The aim of this research was to investigate whether this gap has changed between 2003 and 2010. Method A postal questionnaire based on that used by Cairns et al. was sent to 50% of GDPs in Scotland in March 2010. Results The response rate was 52% (53% male). Some 29% and 55% of respondents had received undergraduate or postgraduate training in child protection respectively. Over two thirds (37%) had suspected child abuse/neglect in one or more of their paediatric patients but only 11% had referred a case. The most common factor affecting the decision to refer was 'lack of certainty of the diagnosis' (74%). Some 77% thought that abused/neglected children had an increased caries increment and 73% of dentists were willing to get involved in detecting neglect. Conclusion Dentists in Scotland appear to be suspecting and referring more cases of child abuse/neglect than previously. The vast majority are willing to get involved in detecting neglect.

Aims Since 2008, in England, all unexpected child deaths undergo a multi-agency investigation with the aim of determining the complete cause of death; followed by review by local Child Death Overview Panels (CDOP). These new processes have yet to be evaluated. This study aims to determine the effectiveness of the multi-agency investigation and CDOP processes in ascertaining causes of death and risk factors following Sudden Unexpected Death in Infancy (SUDI) and to describe the profile of causes and risk factors. Methods We obtained the dates of birth and death of all SUDI cases from one English region, dying between 1 September 2010 and 31 August 2012. We contacted all 10 CDOP for copies of individual case reviews completed using the standard CDOP Form C. We extracted the age, cause of death and presence of modifiable factors for each case from the Form C and created a total family and environmental risk factor score by totalling the risk factors. Results Data were obtained for 65/70 (93%) SUDI cases. 20/65 (31%) deaths were due to medical causes; 21/65 (32%) due to SIDS and 24/65 (37%) classified as unascertained deaths. Reanalysis of case data suggested that 9 deaths were probably due to accidental asphyxia, with 6 of these involving parents co-sleeping with their infant after consuming excessive alcohol. Unascertained deaths had significantly higher total family and environmental risk factor scores (mean 2.6, 95% CI 2.0–3.3) compared to 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%) unascertained deaths were considered to be preventable. There were inadequacies in medical provision identified in 5/20 (25%) of medically explained deaths. Conclusions The new multi-agency child death processes are effective at determining cause of death and risk factors for SUDI but potential asphyxia deaths may not be recognised. Most deaths labelled as unascertained fulfilled diagnostic criteria for SIDS. Many SUDI occurred in families with mental illness, drug or alcohol misuse and chaotic lifestyles and most in unsafe sleep-environments.

Aims Since 2008, in England, all unexpected infant deaths must be investigated jointly by police, health and social services. This study aims to learn of bereaved parents’ and professionals’ experiences of this joint agency approach (JAA) as well as assess the effectiveness of the JAA in determining causes and risk factors for deaths and use this knowledge to improve professional practice. Methods A mixed methods study of JAA investigation of SUDI cases in one English region; involving case note analysis, questionnaires and in–depth interviews with bereaved parents and the relevant professionals. A descriptive study of outcomes of JAA SUDI investigation using Child Death Overview Panel (CDOP) data. Results 23/111 families were recruited giving theoretical saturation. The median time between infants’ deaths and parental study participation was 33 weeks; data collection took place between 2011–3. 25 professionals were interviewed. CDOP Form Cs were obtained for 65/70 (93%) SUDI cases dying during 2010–2. Non–specialist police often arrived at the parents’ home along with the ambulance; increasing parental distress. Parents felt that the JAA provided information about why their baby died but offered minimal emotional support. The joint home visit by police and paediatrician is a key investigative process and most parents found this helpful. Final case discussions were used to discuss relevant risk factors but not to determine the cause of death; in nearly all cases the final cause of death relied on post–mortem examination alone ignoring findings of death scene examinations. Many deaths fitted the diagnostic criteria for SIDS but despite this were labelled as unascertained. Social care were only involved in 13/23 JAA investigations, in two cases without involvement there were safeguarding concerns. Some Coroners were reluctant to share post–mortem examination reports with paediatricians preventing effective JAA investigations. Conclusion Ideally, SUDI investigations should be carried out only by specialist clinicians who do this work frequently and the JAA fully integrated with social care and Coroners’ investigations. There needs to be a clearer system for classifying unexplained SUDI. Police should reconsider their immediate response to SUDI; parents would like more follow–up and bereavement support from professionals.