A longitudinal comparison of emotional, behavioral and attention problems in autistic and typically developing children.

BACKGROUND: Mental health problems are elevated in autistic individuals but there is limited evidence on the developmental course of problems across childhood. We compare the level and growth of anxious-depressed, behavioral and attention problems in an autistic and typically developing (TD) cohort. METHODS: Latent growth curve models were applied to repeated parent-report Child Behavior Checklist data from age 2-10 years in an inception cohort of autistic children (Pathways, N = 397; 84% boys) and a general population TD cohort (Wirral Child Health and Development Study; WCHADS; N = 884, 49% boys). Percentile plots were generated to quantify the differences between autistic and TD children. RESULTS: Autistic children showed elevated levels of mental health problems, but this was substantially reduced by accounting for IQ and sex differences between the autistic and TD samples. There was small differences in growth patterns; anxious-depressed problems were particularly elevated at preschool and attention problems at late childhood. Higher family income predicted lower base-level on all three dimensions, but steeper increase of anxious-depressed problems. Higher IQ predicted lower level of attention problems and faster decline over childhood. Female sex predicted higher level of anxious-depressed and faster decline in behavioral problems. Social-affect autism symptom severity predicted elevated level of attention problems. Autistic girls' problems were particularly elevated relative to their same-sex non-autistic peers. CONCLUSIONS: Autistic children, and especially girls, show elevated mental health problems compared to TD children and there are some differences in predictors. Assessment of mental health should be integrated into clinical practice for autistic children.

Mars and the ESA Science Programme - the case for Mars polar science.

Current plans within the European Space Agency (ESA) for the future investigation of Mars (after the ExoMars programme) are centred around participation in the Mars Sample Return (MSR) programme led by NASA. This programme is housed within the Human and Robotic Exploration (HRE) Directorate of ESA. This White Paper, in response to the Voyage 2050 call, focuses on the important scientific objectives for the investigation of Mars outside the present HRE planning. The achievement of these objectives by Science Directorate missions is entirely consistent with ESA's Science Programme. We illustrate this with a theme centred around the study of the Martian polar caps and the investigation of recent (Amazonian) climate change produced by known oscillations in Mars' orbital parameters. Deciphering the record of climate contained within the polar caps would allow us to learn about the climatic evolution of another planet over the past few to hundreds of millions of years, and also addresses the more general goal of investigating volatile-related dynamic processes in the Solar System.

Performance Scaling in Magnetized Liner Inertial Fusion Experiments.

We present experimental results from the first systematic study of performance scaling with drive parameters for a magnetoinertial fusion concept. In magnetized liner inertial fusion experiments, the burn-averaged ion temperature doubles to 3.1 keV and the primary deuterium-deuterium neutron yield increases by more than an order of magnitude to 1.1×10^{13} (2 kJ deuterium-tritium equivalent) through a simultaneous increase in the applied magnetic field (from 10.4 to 15.9 T), laser preheat energy (from 0.46 to 1.2 kJ), and current coupling (from 16 to 20 MA). Individual parametric scans of the initial magnetic field and laser preheat energy show the expected trends, demonstrating the importance of magnetic insulation and the impact of the Nernst effect for this concept. A drive-current scan shows that present experiments operate close to the point where implosion stability is a limiting factor in performance, demonstrating the need to raise fuel pressure as drive current is increased. Simulations that capture these experimental trends indicate that another order of magnitude increase in yield on the Z facility is possible with additional increases of input parameters.

Morality in autism spectrum disorder: A systematic review.

Moral reasoning and decision making help guide behavior and facilitate interpersonal relationships. Accounts of morality that position commonsense psychology as the foundation of moral development, (i.e., rationalist theories) have dominated research in morality in autism spectrum disorder (ASD). Given the well-documented differences in commonsense psychology among autistic individuals, researchers have investigated whether the development and execution of moral judgement and reasoning differs in this population compared with neurotypical individuals. In light of the diverse findings of investigations of moral development and reasoning in ASD, a summation and critical evaluation of the literature could help make sense of what is known about this important social-cognitive skill in ASD. To that end, we conducted a systematic review of the literature investigating moral decision making among autistic children and adults. Our search identified 29 studies. In this review, we synthesize the research in the area and provide suggestions for future research. Such research could include the application of an alternative theoretical framework to studying morality in autism spectrum disorder that does not assume a deficits-based perspective.

Clinical Reliability of point-of-care tests to support community based acute ambulatory care.

OBJECTIVE: To ensure clinicians can rely on point-of-care testing results, we assessed agreement between point-of-care tests for creatinine, urea, sodium, potassium, calcium, Hb, INR, CRP and subsequent corresponding laboratory tests. PARTICIPANTS: Community-dwelling adults referred to a community-based acute ambulatory care unit. INTERVENTIONS: The Abbott i-STATTM (Hb, clinical chemistry, INR) and the AfinionTM Analyser (CRP) and corresponding laboratory analyses. OUTCOMES: Agreement (Bland-Altman) and bias (Passing-Bablok regression). RESULTS: Among 462 adults we found an absolute mean difference between point-of-care and central laboratory analyses of 6.4g/L (95%LOA -7.9 to +20.6) for haemoglobin, -0.5mmol/L (95%LOA -4.5 to +3.5) for sodium, 0.2mmol/L (95%LOA -0.6 to +0.9) for potassium, 0.0mmol/L (95%LOA -0.3 to +0.3) for calcium, 9.0 µmol/L (95%LOA -18.5 to +36.4) for creatinine, 0.0mmol/L (95%LOA -2.7 to +2.6) for urea, -0.2 (95%LOA -2.4 to +2.0) for INR, -5.0 mg/L (95%LOA -24.4 to +14.4) for CRP. CONCLUSIONS: There was acceptable agreement and bias for these analytes, except for haemoglobin and creatinine.

Recombinant protein purification in baculovirus-infected Rachiplusia nu larvae: An approach towards a rational design of downstream processing strategies based on chromatographic behavior of proteins.

Expression of recombinant proteins with baculovirus-infected insect larvae is a scarcely investigated alternative in comparison to that in insect cell lines, a system with growing popularity in the field of biotechnology. The aim of this study was to investigate the chromatographic behavior and physicochemical properties of the proteome of Rachiplusia nu larvae infected with recombinant Autographa californica multiple nucleopolyhedrosis virus (AcMNPV), in order to design rational purification strategies for the expression of heterologous proteins in this very complex and little-known system, based on the differential absorption between target recombinant proteins and the system's contaminating ones. Two-dimensional (2D) gel electrophoresis showed differences in the protein patterns of infected and non-infected larvae. Hydrophobic interaction matrices adsorbed the bulk of larval proteins, thus suggesting that such matrices are inappropriate for this system. Only 0.03% and 2.9% of the total soluble protein from the infected larval extract was adsorbed to CM-Sepharose and SP-Sepharose matrices, respectively. Immobilized metal ion affinity chromatography represented a solid alternative because it bound only 1.4% of the total protein, but would increase the cost of the purification process. We concluded that cation-exchange chromatography is the best choice for easy purification of high-isoelectric-point proteins and proteins with arginine tags, since very few contaminating proteins co-eluted with our target protein.

Traditional plant functional groups explain variation in economic but not size-related traits across the tundra biome.

AIM: Plant functional groups are widely used in community ecology and earth system modelling to describe trait variation within and across plant communities. However, this approach rests on the assumption that functional groups explain a large proportion of trait variation among species. We test whether four commonly used plant functional groups represent variation in six ecologically important plant traits. LOCATION: Tundra biome. TIME PERIOD: Data collected between 1964 and 2016. MAJOR TAXA STUDIED: 295 tundra vascular plant species. METHODS: We compiled a database of six plant traits (plant height, leaf area, specific leaf area, leaf dry matter content, leaf nitrogen, seed mass) for tundra species. We examined the variation in species-level trait expression explained by four traditional functional groups (evergreen shrubs, deciduous shrubs, graminoids, forbs), and whether variation explained was dependent upon the traits included in analysis. We further compared the explanatory power and species composition of functional groups to alternative classifications generated using post hoc clustering of species-level traits. RESULTS: Traditional functional groups explained significant differences in trait expression, particularly amongst traits associated with resource economics, which were consistent across sites and at the biome scale. However, functional groups explained 19% of overall trait variation and poorly represented differences in traits associated with plant size. Post hoc classification of species did not correspond well with traditional functional groups, and explained twice as much variation in species-level trait expression. MAIN CONCLUSIONS: Traditional functional groups only coarsely represent variation in well-measured traits within tundra plant communities, and better explain resource economic traits than size-related traits. We recommend caution when using functional group approaches to predict tundra vegetation change, or ecosystem functions relating to plant size, such as albedo or carbon storage. We argue that alternative classifications or direct use of specific plant traits could provide new insights for ecological prediction and modelling.

Identification of Aspergillus and Mucorales in formalin-fixed, paraffin-embedded tissue samples: Comparison of specific and broad-range fungal qPCR assays.

Establishing the etiology of invasive fungal infections is important to guide therapeutic options and for epidemiologic purposes. Formalin-fixed, paraffin-embedded (FFPE) tissue specimens from patients with proven invasive fungal infections are valuable to determine the etiology of systemic fungal infections. We compared different polymerase chain reaction (PCR) amplification strategies from FFPE tissue blocks to identify agents of invasive fungal infections. We found that specific PCR assays show superior sensitivity in the identification of DNA of Mucorales and Aspergillus and mixed infections caused by both as compared to broad-range PCR assays. Shorter amplicon lengths and less detection of contaminating fungal DNA are potential factors involved. However, detection of fungal DNA by highly sensitive specific PCR assays in the absence of demonstration of fungal elements in tissue suggests that PCR results should be interpreted in the context of the histopathology and clinical findings.

Epithelial sodium channel blockade and new ß-ENaC polymorphisms among normotensive and hypertensive adult Nigerians.

We sought to determine the effect of amiloride on blood pressure (BP) and the presence of polymorphisms of the ß-subunit of the epithelial sodium channel (ENaC) among normotensive (NT) and hypertensive (HT) Nigerians. Healthy volunteers-47 NT and 53 age-matched HT were recruited after giving informed consent. Subjects were salt-loaded with 200 mmol of NaCl daily for 5 days. Following a week washout period, salt-loading was repeated in addition to the administration of 5 mg amiloride daily for five days. Blood pressure, plasma and urine electrolytes were measured at baseline, after salt-loading and after salt-loading plus amiloride. PCR amplicons were sequenced for ß-ENaC polymorphisms. Salt-loading led to a significant increase (p < 0.05) in SBP among NT and HT and in DBP (p < 0.001) only among HT. Amiloride reduced SBP and DBP to below baseline levels in NT (p < 0.05) and HT (p < 0.001) subjects. Five of the subjects had the ß-T594M polymorphism, HT 3/53; NT 2/47 (p = 0.75). Four previously unreported ß-ENaC mutations were recorded: E632V and E636V, respectively, among two HT subjects, D638Y in another HT and L628Q in one NT subject. We showed the presence of ß-ENaC polymorphisms among our populace and the possible usefulness of amiloride as a single antihypertensive among Nigerians.

Final results of a multi-institutional phase II trial of reirradiation with concurrent weekly cisplatin and cetuximab for recurrent or second primary squamous cell carcinoma of the head and neck.

Background: The optimal regimen of chemotherapy and reirradiation (re-XRT) for recurrent head and neck squamous cell carcinoma (HNSCC) is controversial. We report the final outcomes of a multicenter phase II trial evaluating cetuximab and cisplatin-based chemotherapy concurrent with re-XRT for patients with recurrent HNSCC. Materials and methods: Patients with unresectable recurrent disease or positive margins after salvage surgery arising within a previously irradiated field with KPS ≥ 70 were eligible for this trial. Cetuximab 400 mg/m2 was delivered as a loading dose in week 1 followed by weekly cetuximab 250 mg/m2 and cisplatin 30 mg/m2 concurrent with 6 weeks of intensity-modulated radiotherapy to a dose of 60-66 Gy in 30 daily fractions. Patients who previously received both concurrent cetuximab and cisplatin with radiation or who received radiotherapy less than 6 months prior were ineligible. Results: From 2009 to 2013, 48 patients enrolled on this trial, 2 did not receive any protocol treatment. Of the remaining 46 patients, 34 were male and 12 female, with a median age of 62 years (range 36-85). Treatment was feasible and only 1 patient did not complete the treatment course. Common grade 3 or higher acute toxicities were lymphopenia (46%), pain (22%), dysphagia (13%), radiation dermatitis (13%), mucositis (11%) and anorexia (11%). There were no grade 5 acute toxicities. Eight grade 3 late toxicities were observed, four of which were swallowing related. With a median follow-up of 1.38 years, the 1-year overall survival (OS) was 60.4% and 1-year recurrence-free survival was 34.1%. On univariate analysis, OS was significantly improved with young age (P = 0.01). OS was not associated with radiation dose, surgery before re-XRT or interval from prior XRT. Conclusions: Concurrent cisplatin and cetuximab with re-XRT is feasible and offers good treatment outcomes for patients with high-risk features. Younger patients had significantly improved OS. ClinicalTrials.Gov Identifier: NCT00833261.

RePHILL: protocol for a randomised controlled trial of pre-hospital blood product resuscitation for trauma.

OBJECTIVES: To describe the 'Resuscitation with Pre-HospItaL bLood products' trial (RePHILL) - a multi-centre randomised controlled trial of pre-hospital blood product (PHBP) administration vs standard care for traumatic haemorrhage. BACKGROUND: PHBP are increasingly used for pre-hospital trauma resuscitation despite a lack of robust evidence demonstrating superiority over crystalloids. Provision of PHBP carries additional logistical and regulatory implications, and requires a sustainable supply of universal blood components. METHODS: RePHILL is a multi-centre, two-arm, parallel group, open-label, phase III randomised controlled trial currently underway in the UK. Patients attended by a pre-hospital emergency medical team, with traumatic injury and hypotension (systolic blood pressure <90 mmHg or absent radial pulse) believed to be due to traumatic haemorrhage are eligible. Exclusion criteria include age <16 years, blood product receipt on scene prior to randomisation, Advanced Medical Directive forbidding blood product administration, pregnancy, isolated head injury and prisoners. A total of 490 patients will be recruited in a 1 : 1 ratio to receive either the intervention (up to two units of red blood cells and two units of lyophilised plasma) or the control (up to four boluses of 250 mL 0.9% saline). The primary outcome measure is a composite of failure to achieve lactate clearance of ≥20%/h over the first 2 hours after randomisation and all-cause mortality between recruitment and discharge from the primary receiving facility to non-acute care. Secondary outcomes include pre-hospital time, coagulation indices, in-hospital transfusion requirements and morbidity. RESULTS: Pilot study recruitment began in December 2016. Approval to proceed to the main trial was received in June 2017. Recruitment is expected to continue until 2020. CONCLUSIONS: RePHILL will provide high-quality evidence regarding the efficacy and safety of PHBP resuscitation for trauma.

Research needs in breast cancer.

New research questions emerge as medical needs continue to evolve and as we improve our understanding of cancer biology and treatment of malignancies. Although significant advances have been made in some areas of breast cancer research resulting in improvements in therapies and outcomes over the last few decades, other areas have not benefited to the same degree and we continue to have many gaps in our knowledge. This article summarizes the 12 short and medium-term clinical research needs in breast cancer deemed as priorities in 2016 by a panel of experts, in an attempt to focus and accelerate future research in the most needed areas: (i) de-escalate breast cancer therapies in early breast cancer without sacrificing outcomes; (ii) explore optimal adjuvant treatment durations; (iii) develop better tools and strategies to identify patients with genetic predisposition; (iv) improve care in young patients with breast cancer; (v) develop tools to speed up drug development in biomarker-defined populations; (vi) identify and validate targets that mediate resistance to chemotherapy, endocrine therapy and anti-HER2 therapies; (vii) evaluate the efficacy of local-regional treatments for metastatic disease; (viii) better define the optimal sequence of treatments in the metastatic setting; (ix) evaluate the clinical impact of intra-patient heterogeneity (intra-tumor, inter-tumor and inter-lesion heterogeneity); (x) better understand the biology and identify new targets in triple-negative breast cancer; (xi) better understand immune surveillance in breast cancer and further develop immunotherapies; and (xii) increase survivorship research efforts including supportive care and quality of life.

De-escalating and escalating treatments for early-stage breast cancer: the St. Gallen International Expert Consensus Conference on the Primary Therapy of Early Breast Cancer 2017.

The 15th St. Gallen International Breast Cancer Conference 2017 in Vienna, Austria reviewed substantial new evidence on loco-regional and systemic therapies for early breast cancer. Treatments were assessed in light of their intensity, duration and side-effects, seeking where appropriate to escalate or de-escalate therapies based on likely benefits as predicted by tumor stage and tumor biology. The Panel favored several interventions that may reduce surgical morbidity, including acceptance of 2 mm margins for DCIS, the resection of residual cancer (but not baseline extent of cancer) in women undergoing neoadjuvant therapy, acceptance of sentinel node biopsy following neoadjuvant treatment of many patients, and the preference for neoadjuvant therapy in HER2 positive and triple-negative, stage II and III breast cancer. The Panel favored escalating radiation therapy with regional nodal irradiation in high-risk patients, while encouraging omission of boost in low-risk patients. The Panel endorsed gene expression signatures that permit avoidance of chemotherapy in many patients with ER positive breast cancer. For women with higher risk tumors, the Panel escalated recommendations for adjuvant endocrine treatment to include ovarian suppression in premenopausal women, and extended therapy for postmenopausal women. However, low-risk patients can avoid these treatments. Finally, the Panel recommended bisphosphonate use in postmenopausal women to prevent breast cancer recurrence. The Panel recognized that recommendations are not intended for all patients, but rather to address the clinical needs of the majority of common presentations. Individualization of adjuvant therapy means adjusting to the tumor characteristics, patient comorbidities and preferences, and managing constraints of treatment cost and access that may affect care in both the developed and developing world.

Relationship between IHC4 score and response to neo-adjuvant chemotherapy in estrogen receptor-positive breast cancer.

AIMS: To determine whether IHC4 score assessed on pre-treatment core biopsies (i) predicts response to neo-adjuvant chemotherapy in ER-positive (ER+) breast cancer; (ii) provides more predictive information than Ki67 alone. METHODS: 113 patients with ER+ primary breast cancer treated with neo-adjuvant chemotherapy at the Royal Marsden Hospital between 2002 and 2010 were included in the study. Pathologic assessment of the excision specimen was made for residual disease. IHC4 was determined on pre-treatment core biopsies, blinded to clinical outcome, by immunohistochemistry using quantitative scoring of ER (H-score), PgR (%) and Ki67 (%). Determination of HER2 status was made by immunohistochemistry and fluorescent in situ hybridization for 2+ cases. IHC4 and Ki67 scores were tested for their association with pathological complete response (pCR) rate and residual cancer burden (RCB) score. RESULTS: 18 (16%) of the 113 patients and 8 (9%) of the 88 HER2-ve cases achieved pCR. Ki67 and IHC4 score were both positively associated with achievement of pCR (P < 10-7 and P < 10-9, respectively) and RCB0+1 (P < 10-5 and P < 10-9, respectively) following neo-adjuvant chemotherapy in all patients. Rates of pCR+RCB1 were 45 and 66% in the highest quartiles of Ki67 and IHC4 scores, respectively. In ER+HER2-ve cases, pCR+RCB1 rates were 35% and in the highest quartile of both Ki67 and IHC4. There were no pCRs in the lower half of IHC4 or Ki67 scores. CONCLUSIONS: IHC4 was strongly predictive of pCR or near pCR in ER+ breast cancers following neo-adjuvant chemotherapy. Ki67 was an important component of this predictive ability, but was not as predictive as IHC4.

Functional and neurochemical characterization of angiotensin type 1A receptor-expressing neurons in the nucleus of the solitary tract of the mouse.

Angiotensin II acts via two main receptors within the central nervous system, with the type 1A receptor (AT1AR) most widely expressed in adult neurons. Activation of the AT1R in the nucleus of the solitary tract (NTS), the principal nucleus receiving central synapses of viscerosensory afferents, modulates cardiovascular reflexes. Expression of the AT1R occurs in high density within the NTS of most mammals, including humans, but the fundamental electrophysiological and neurochemical characteristics of the AT1AR-expressing NTS neurons are not known. To address this, we have used a transgenic mouse, in which the AT1AR promoter drives expression of green fluorescent protein (GFP). Approximately one-third of AT1AR-expressing neurons express the catecholamine-synthetic enzyme tyrosine hydroxylase (TH), and a subpopulation of these stained for the transcription factor paired-like homeobox 2b (Phox2b). A third group, comprising approximately two-thirds of the AT1AR-expressing NTS neurons, showed Phox2b immunoreactivity alone. A fourth group in the ventral subnucleus expressed neither TH nor Phox2b. In whole cell recordings from slices in vitro, AT1AR-GFP neurons exhibited voltage-activated potassium currents, including the transient outward current and the M-type potassium current. In two different mouse strains, both AT1AR-GFP neurons and TH-GFP neurons showed similar AT1AR-mediated depolarizing responses to superfusion with angiotensin II. These data provide a comprehensive description of AT1AR-expressing neurons in the NTS and increase our understanding of the complex actions of this neuropeptide in the modulation of viscerosensory processing.

Hospital outcomes and long-term survival after referral to a specialized weaning unit.

BACKGROUND.: Prolonged invasive mechanical ventilation (IMV) is a frequent challenge, and an increasing number of patients are transferred from intensive care units to long-term acute care hospitals or specialized weaning units. There are few published data for discharge home rates, use of noninvasive ventilation (NIV), or long-term survival. METHODS.: A case-note and database review was conducted of patients admitted to a UK national specialized weaning unit for weaning from IMV between 1992 and 2012. Patients were grouped into diagnostic categories according to the predominant cause of weaning failure. Weaning outcomes and long-term survival were assessed according to diagnostic group and mode of ventilation on discharge. RESULTS.: Four hundred and fifty-eight patients were transferred for weaning from IMV. Four hundred and seventeen (91%) survived to hospital discharge, of whom at least 343 (82%) were ultimately discharged to their own home. Three hundred and thirty (72%) weaned from IMV, of whom 142 weaned from all ventilation and 188 weaned to nocturnal NIV. Weaning success was highest for patients with chronic obstructive pulmonary disease and chest wall disorders. Median survival from unit discharge was 25 months (interquartile range 5-74), with the longest survival seen for patients discharged with nocturnal NIV [37 (12-81) months]. CONCLUSIONS.: These results confirm successful weaning outcomes for patients transferred to a specialized weaning and long-term ventilation service. In contrast to other service models, most patients achieved discharge to their own home.

Treatment of severe, chronic hand eczema: results from a UK-wide survey.

Treatment of severe hand eczema (HE) that is resistant to topical potent corticosteroid treatment is challenging. In 2013, we surveyed 194 UK dermatologists to obtain information about their usual treatment pathways to inform the choice of the comparator in a trial of alitretinoin in severe HE (ALPHA trial); the results indicated that the treatment approaches favoured by UK dermatologists differ. Psoralen combined with ultraviolet A (PUVA) and alitretinoin were identified as the most frequent first-line treatment options for hyperkeratotic HE, whereas oral corticosteroids were identified as the most frequent first-line treatment for vesicular HE, followed by PUVA and alitretinoin. In terms of potential adverse effects of long-term or repeated use, oral steroids and ciclosporin A were reported to cause most concern. There is uncertainty about which treatment gives the best short and long-term outcomes, because of a lack of definitive randomised controlled trials evaluating the effectiveness of different treatment pathways in severe HE.

Adjuvant bisphosphonates in early breast cancer: consensus guidance for clinical practice from a European Panel.

Bisphosphonates have been studied in randomised trials in early breast cancer to investigate their ability to prevent cancer treatment-induced bone loss (CTIBL) and reduce the risk of disease recurrence and metastasis. Treatment benefits have been reported but bisphosphonates do not currently have regulatory approval for either of these potential indications. This consensus paper provides a review of the evidence and offers guidance to breast cancer clinicians on the use of bisphosphonates in early breast cancer. Using the nominal group methodology for consensus, a systematic review of the literature was augmented by a workshop held in October 2014 for breast cancer and bone specialists to present and debate the available pre-clinical and clinical evidence for the use of adjuvant bisphosphonates. This was followed by a questionnaire to all members of the writing committee to identify areas of consensus. The panel recommended that bisphosphonates should be considered as part of routine clinical practice for the prevention of CTIBL in all patients with a T score of <-2.0 or ≥2 clinical risk factors for fracture. Compelling evidence from a meta-analysis of trial data of >18,000 patients supports clinically significant benefits of bisphosphonates on the development of bone metastases and breast cancer mortality in post-menopausal women or those receiving ovarian suppression therapy. Therefore, the panel recommends that bisphosphonates (either intravenous zoledronic acid or oral clodronate) are considered as part of the adjuvant breast cancer treatment in this population and the potential benefits and risks discussed with relevant patients.

Clinical utility of the IHC4+C score in oestrogen receptor-positive early breast cancer: a prospective decision impact study.

BACKGROUND: Most oestrogen receptor (ER)-positive early breast cancer diagnosed today is highly curable with multimodality treatment. Systemic adjuvant treatments including endocrine therapy and chemotherapy have made a significant contribution to the increasing cure rates over the past three decades. However not all women will require chemotherapy. The IHC4+C score is a prognostic tool that integrates four immunohistochemical measures with clinicopathological features to estimate the residual risk of distant recurrence at 10 years in post-menopausal women with ER-positive breast cancer who have received 5 years of endocrine therapy. Retrospective studies indicate that the test can identify a set of women that are at such low risk of recurrence that chemotherapy can be of little benefit. METHODS: In this study, 124 patients were prospectively selected from the multidisciplinary team meeting between January 2013 and April 2014 for IHC4+C testing. Adjuvant systemic treatment recommendations by clinicians were recorded without and with the availability of the score in addition to the patient's decision. RESULTS: There was concordance in the MDT's recommendation without and with the availability of the score in 73% of cases. Clinicians recommended chemotherapy or at least its discussion to 74 (59%) patients, which fell to 32 (34%) patients after the IHC4+C score was made available, sparing one in four tested patients a chemotherapy recommendation, along with its toxicity and expense. CONCLUSION: This decision impact study shows that when used by clinicians in the multidisciplinary team meeting for adjuvant decision-making, a significant proportion of patients are spared chemotherapy recommendations.

Impact of KRAS codon subtypes from a randomised phase II trial of selumetinib plus docetaxel in KRAS mutant advanced non-small-cell lung cancer.

BACKGROUND: Selumetinib (AZD6244, ARRY-142886)+docetaxel increases median overall survival (OS) and significantly improves progression-free survival (PFS) and objective response rate (ORR) compared with docetaxel alone in patients with KRAS mutant, stage IIIB/IV non-small-cell lung cancer (NSCLC; NCT00890825). METHODS: Retrospective analysis of OS, PFS, ORR and change in tumour size at week 6 for different sub-populations of KRAS codon mutations. RESULTS: In patients receiving selumetinib+docetaxel and harbouring KRAS G12C or G12V mutations there were trends towards greater improvement in OS, PFS and ORR compared with other KRAS mutations. CONCLUSION: Different KRAS mutations in NSCLC may influence selumetinib/docetaxel sensitivity.