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1.
Artigo em Inglês | MEDLINE | ID: mdl-31502222

RESUMO

Only a few analytical techniques are available for the characterization of mechanochemical synthetic reaction products. We demonstrate here that DESI-MS is a powerful technique for this purpose, combining the selectivity of MS-based assays with the simplicity and in situ analysis capability of ambient ionization methods. In this work, we report that auranofin, a gold-based drug, and its precursor triethylphosphine gold(I) chloride undergo a complex array of ligand exchange/scrambling reactions with thiol-containing amino acids in the solid state. The products were readily characterized by DESI-MS analysis from the solid-phase reaction, clearly exhibiting ligand exchange and scrambling, with independent confirmation by solid state 13C-NMR. The thioglucose and triethylphosphine moieties exchanged with cysteine and its derivatives, whereas the glutathione replaced 2,3,4,6-tetra-o-acetyl-ß-1-D-glucopyranose only. It was concluded that ligand exchange and scrambling reactions can be carried out in the solid state, and some of the unique products reported in this study can be conveniently prepared through mechanochemical synthesis in good yields (> 98%), as demonstrated by synthesis of (L-cysteinato-S)-triethylphosphine gold(I) from triethylphosphine gold(I) chloride and L-cysteine.

3.
Sci Transl Med ; 11(506)2019 Aug 21.
Artigo em Inglês | MEDLINE | ID: mdl-31434758

RESUMO

Treatment of autoimmune and inflammatory diseases typically involves immune suppression. In an opposite strategy, we show that administration of the highly inflammatory erythrocyte-specific antibody Ter119 into mice remodels the monocyte cellular landscape, leading to resolution of inflammatory disease. Ter119 with intact Fc function was unexpectedly therapeutic in the K/BxN serum transfer model of arthritis. Similarly, it rapidly reversed clinical disease progression in collagen antibody-induced arthritis (CAIA) and collagen-induced arthritis and completely corrected CAIA-induced increase in monocyte Fcγ receptor II/III expression. Ter119 dose-dependently induced plasma chemokines CCL2, CCL5, CXCL9, CXCL10, and CCL11 with corresponding alterations in monocyte percentages in the blood and liver within 24 hours. Ter119 attenuated chemokine production from the synovial fluid and prevented the accumulation of inflammatory cells and complement components in the synovium. Ter119 could also accelerate the resolution of hypothermia and pulmonary edema in an acute lung injury model. We conclude that this inflammatory anti-erythrocyte antibody simultaneously triggers a highly efficient anti-inflammatory effect with broad therapeutic potential.

4.
Radiother Oncol ; 2019 Aug 17.
Artigo em Inglês | MEDLINE | ID: mdl-31431385

RESUMO

PURPOSE: To assess the cosmetic impact of breast conserving surgery (BCS), whole breast irradiation (WBI) fractionation and tumour bed boost (TBB) use in a phase III trial for women with ductal carcinoma in situ (DCIS) of the breast. MATERIALS AND METHODS: Baseline and 3-year cosmesis were assessed using the European Organization for Research and Treatment of Cancer (EORTC) Cosmetic Rating System and digital images in a randomised trial of non-low risk DCIS treated with postoperative WBI +/- TBB. Baseline cosmesis was assessed for four geographic clusters of treating centres. Cosmetic failure was a global score of fair or poor. Cosmetic deterioration was a score change from excellent or good at baseline to fair or poor at three years. Odds ratios for cosmetic deterioration by WBI dose-fractionation and TBB use were calculated for both scoring systems. RESULTS: 1608 women were enrolled from 11 countries between 2007 and 2014. 85-90% had excellent or good baseline cosmesis independent of geography or assessment method. TBB (16 Gy in 8 fractions) was associated with a >2-fold risk of cosmetic deterioration (p < 0.001). Hypofractionated WBI (42.5 Gy in 16 fractions) achieved statistically similar 3-year cosmesis compared to conventional WBI (50 Gy in 25 fractions) (p ≥ 0.18). The adverse impact of a TBB was not significantly associated with WBI fractionation (interaction p ≥ 0.30). CONCLUSIONS: Cosmetic failure from BCS was similar across international jurisdictions. A TBB of 16 Gy increased the rate of cosmetic deterioration. Hypofractionated WBI achieved similar 3-year cosmesis as conventional WBI in women treated with BCS for DCIS.

5.
Proc Natl Acad Sci U S A ; 116(29): 14557-14562, 2019 Jul 16.
Artigo em Inglês | MEDLINE | ID: mdl-31262814

RESUMO

A symmetric origin for bacterial ferredoxins was first proposed over 50 y ago, yet, to date, no functional symmetric molecule has been constructed. It is hypothesized that extant proteins have drifted from their symmetric roots via gene duplication followed by mutations. Phylogenetic analyses of extant ferredoxins support the independent evolution of N- and C-terminal sequences, thereby allowing consensus-based design of symmetric 4Fe-4S molecules. All designs bind two [4Fe-4S] clusters and exhibit strongly reducing midpoint potentials ranging from -405 to -515 mV. One of these constructs efficiently shuttles electrons through a designed metabolic pathway in Escherichia coli These finding establish that ferredoxins consisting of a symmetric core can be used as a platform to design novel electron transfer carriers for in vivo applications. Outer-shell asymmetry increases sequence space without compromising electron transfer functionality.

6.
J Med Chem ; 62(15): 6972-6984, 2019 Aug 08.
Artigo em Inglês | MEDLINE | ID: mdl-31283227

RESUMO

4-(Pyrimidin-4-yl)morpholines are privileged pharmacophores for PI3K and PIKKs inhibition by virtue of the morpholine oxygen, both forming the key hydrogen bonding interaction and conveying selectivity over the broader kinome. Key to the morpholine utility as a kinase hinge binder is its ability to adopt a coplanar conformation with an adjacent aromatic core favored by the morpholine nitrogen nonbonding pair of electrons interacting with the electron deficient pyrimidine π-system. Few selective morpholine replacements have been identified to date. Herein we describe the discovery of a potent non-nitrogen containing morpholine isostere with the ability to mimic this conformation and its application in a potent selective dual inhibitor of mTORC1 and mTORC2 (29b).

7.
Breast Cancer Res Treat ; 177(2): 497-505, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31168758

RESUMO

PURPOSE: This study aims to examine the differences in characteristics, treatment and survival between Asian and European women diagnosed with stage I-III breast cancer in New Zealand. METHODS: The studied population included European women and Asian women diagnosed with stage I-III breast cancer between June 2000 and May 2013 identified from the combined Waikato and Auckland Breast Cancer Registers. Characteristics and treatment were compared between Asian and European women. Kaplan-Meier method was used to examine the survival difference. Cox proportional hazards model was used to estimate the hazard ratio (HR) of mortality. RESULTS: The studied cohort included 8608 European and 949 Asian women. Asian women were younger, had less comorbidities and were less likely to be obese than European women. Asian women were more likely to have grade 3, larger and HER2+ breast cancers. Asian women were more likely to receive mastectomy, less likely to have reconstruction after mastectomy, less likely to have chemotherapy, less likely to be treated with trastuzumab if HER2+, and had better adherence to endocrine therapy (adjusted odds ratio: 1.54; 95% CI 1.22-1.93). Asian women had better cancer-specific survival and all-cause survival than European women. The adjusted HR of cancer-specific mortality and all-cause mortality were 0.64 (95% CI 0.49-0.82) and 0.68 (95% CI 0.55-0.84), respectively. CONCLUSIONS: Asian women are more likely to have high grade, larger and HER2+ breast cancers than European women. In spite of this, they had better breast cancer outcomes. Possible explanations include the differences in adherence to endocrine therapy, age, BMI and comorbidities.

8.
Br J Cancer ; 121(2): 180-192, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31213659

RESUMO

BACKGROUND: Height and body mass index (BMI) are associated with higher ovarian cancer risk in the general population, but whether such associations exist among BRCA1/2 mutation carriers is unknown. METHODS: We applied a Mendelian randomisation approach to examine height/BMI with ovarian cancer risk using the Consortium of Investigators for the Modifiers of BRCA1/2 (CIMBA) data set, comprising 14,676 BRCA1 and 7912 BRCA2 mutation carriers, with 2923 ovarian cancer cases. We created a height genetic score (height-GS) using 586 height-associated variants and a BMI genetic score (BMI-GS) using 93 BMI-associated variants. Associations were assessed using weighted Cox models. RESULTS: Observed height was not associated with ovarian cancer risk (hazard ratio [HR]: 1.07 per 10-cm increase in height, 95% confidence interval [CI]: 0.94-1.23). Height-GS showed similar results (HR = 1.02, 95% CI: 0.85-1.23). Higher BMI was significantly associated with increased risk in premenopausal women with HR = 1.25 (95% CI: 1.06-1.48) and HR = 1.59 (95% CI: 1.08-2.33) per 5-kg/m2 increase in observed and genetically determined BMI, respectively. No association was found for postmenopausal women. Interaction between menopausal status and BMI was significant (Pinteraction < 0.05). CONCLUSION: Our observation of a positive association between BMI and ovarian cancer risk in premenopausal BRCA1/2 mutation carriers is consistent with findings in the general population.

9.
Exp Eye Res ; 186: 107706, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31226338

RESUMO

Glaucoma is the leading cause of irreversible blindness worldwide. Recently, estrogen deficiencies caused by early menopause, alterations in estrogen signaling via mutations in estrogen receptors, and polymorphisms along estrogen metabolic pathways have all been linked to an increased risk of developing glaucoma. Here, we examined how menopause and age impact visual function and retinal structure in an experimental model of glaucoma. Young (3-4 months) and aged (9-10 months) female Brown Norway rats were divided into pre- and post-menopausal cohorts by surgically inducing menopause via ovariectomy (OVX). After six weeks, ocular hypertension (OHT) was induced unilaterally for a period of eight weeks. Four cohorts were successfully followed to eight weeks: young sham (n = 8), young OVX (n = 9), aged sham (n = 10), and aged OVX (n = 11) animals. Intraocular pressure (IOP) was monitored weekly in all groups. Prior to inducing OHT (baseline) and at four and eight weeks after inducing OHT, we assessed visual acuity via the optomotor response (OMR) and retinal structure using optical coherence tomography (OCT). OHT decreased the OMR in all cohorts. We found that spatial frequency thresholds decreased by 54% in OVX animals after OHT compared to sham animals after OHT, regardless of age (p < 0.001). We also found thinning of the retinal nerve fiber layer (RNFL) and loss of total retinal thickness after induction of OHT. Aged animals had more thinning of the RNFL and loss of total retinal thickness compared to young animals (p < 0.001). Overall, OHT caused significant changes in visual function and retinal structure. Observing that OVX in young and aged animals further decreased spatial frequency thresholds after OHT suggests that an estrogen deficiency may intensify visual impairment after OHT.

10.
Respir Res ; 20(1): 99, 2019 May 22.
Artigo em Inglês | MEDLINE | ID: mdl-31118031

RESUMO

BACKGROUND: Recurrent and persistent infections are known to affect airways of patients with Primary Immunodeficiency despite appropriate replacement immunoglobulin serum levels. Interestingly, patients with Chronic Obstructive Pulmonary Disease or with non-CF bronchiectasis also show similar susceptibility to such infections. This may be due to the limited availability of immunoglobulins from the systemic circulation in the conductive airways, resulting in local immunodeficiency. Topical application of nebulized plasma-derived immunoglobulins may represent a means to address this deficiency. In this study, we assessed the feasibility of nebulizing plasma-derived immunoglobulins and delivering them into the airways of rats and non-human primates. METHODS: Distinct human plasma-derived immunoglobulin isotype preparations were nebulized with an investigational eFlow® nebulizer and analyzed in vitro or deposited into animals. Biochemical and immunohistological analysis of nebulized immunoglobulins were then performed. Lastly, efficacy of topically applied human plasma-derived immunoglobulins was assessed in an acute Streptococcus pneumoniae respiratory infection in mice. RESULTS: Characteristics of the resulting aerosols were comparable between preparations, even when using solutions with elevated viscosity. Neither the structural integrity nor the biological function of nebulized immunoglobulins were compromised by the nebulization process. In animal studies, immunoglobulins levels were assessed in plasma, broncho-alveolar lavages (BAL) and on lung sections of rats and non-human primates in samples collected up to 72 h following application. Nebulized immunoglobulins were detectable over 48 h in the BAL samples and up to 72 h on lung sections. Immunoglobulins recovered from BAL fluid up to 24 h after inhalation remained structurally and functionally intact. Importantly, topical application of human plasma-derived immunoglobulin G into the airways of mice offered significant protection against acute pneumococcal pneumonia. CONCLUSION: Taken together our data demonstrate the feasibility of topically applying plasma-derived immunoglobulins into the lungs using a nebulized liquid formulation. Moreover, topically administered human plasma-derived immunoglobulins prevented acute respiratory infection.

11.
Mucosal Immunol ; 12(4): 1013-1024, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31105268

RESUMO

Recurrent and persistent airway infections remain prevalent in patients with primary immunodeficiency (PID), despite restoration of serum immunoglobulin levels by intravenous or subcutaneous plasma-derived IgG. We investigated the effectiveness of different human Ig isotype preparations to protect mice against influenza when delivered directly to the respiratory mucosa. Four polyvalent Ig preparations from pooled plasma were compared: IgG, monomeric IgA (mIgA), polymeric IgA-containing IgM (IgAM) and IgAM associated with the secretory component (SIgAM). To evaluate these preparations, a transgenic mouse expressing human FcαRI/CD89 within the myeloid lineage was created. CD89 was expressed on all myeloid cells in the lung and blood except eosinophils, reflecting human CD89 expression. Intranasal administration of IgA-containing preparations was less effective than IgG in reducing pulmonary viral titres after infection of mice with A/California/7/09 (Cal7) or the antigenically distant A/Puerto Rico/8/34 (PR8) viruses. However, IgA reduced weight loss and inflammatory mediator expression. Both IgG and IgA protected mice from a lethal dose of PR8 virus and for mIgA, this effect was partially CD89 dependent. Our data support the beneficial effect of topically applied Ig purified from pooled human plasma for controlling circulating and non-circulating influenza virus infections. This may be important for reducing morbidity in PID patients.

12.
J Med Screen ; : 969141319844801, 2019 May 08.
Artigo em Inglês | MEDLINE | ID: mdl-31068074

RESUMO

OBJECTIVE: To compare characteristics and survival of New Zealand European, Maori, and Pacific women with screen-detected vs. non-screen-detected breast cancer. METHODS: Women aged 45-69 diagnosed with invasive breast cancer between January 2005 and May 2013 were identified from the Waikato and Auckland Breast Cancer Registries. Patient demographics and tumour characteristics were described by detection mode and ethnicity. Kaplan-Meier method was used to estimate the five-year breast cancer-specific survival of women with stage I-III breast cancer by ethnicity and detection mode. RESULTS: Women with screen-detected cancers were older, had smaller tumours, fewer stage IV (0.8% vs. 7.6%), fewer high grade (16.8% vs. 39.0%), and fewer lymph node positive diseases (26.3% vs. 51.5%) than women with non-screen-detected cancers. There were more Luminal A (70.0% vs. 54.0%), fewer human epidermal growth factor receptor 2 positive non-Luminal (4.4% vs. 8.8%), and fewer triple negative cases (7.0% vs. 13.8%) in screen-detected than non-screen-detected cancers. If not screen detected, 22.7% of breast cancers in Pacific women were stage IV compared with 2.4% if screen detected. If not screen detected, the five-year breast cancer-specific survival was 91.1% for New Zealand European women, 84.2% for Maori women, and 80.2% for Pacific women (p-value <0.001). For screen-detected breast cancer, survival between different ethnic groups was similar. CONCLUSIONS: Breast cancers detected through screening are diagnosed at an earlier stage and have a greater proportion of subtypes, with better outcome. Variations in survival for Maori and Pacific women are only found in women with non-screen-detected breast cancer.

13.
J Natl Cancer Inst ; 2019 Apr 05.
Artigo em Inglês | MEDLINE | ID: mdl-30949688

RESUMO

BACKGROUND: Loss-of-fuction variants in RAD51C are associated with familial ovarian cancer, but its role in hereditary breast cancer remains unclear. The aim of this study was to couple breast tumor sequencing with case/control data to clarify the contribution of RAD51C to hereditary breast cancer. METHODS: RAD51C was sequenced in 3080 breast cancer index cases that were negative in BRCA1/2 clinical tests and 4840 population-matched cancer-free controls. Pedigree and pathology data were analysed. Nine breast cancers and one ovarian cancer from RAD51C variant carriers were sequenced to identify bi-alleic inactivation of RAD51C, copy number variation, mutational signatures and the spectrum of somatic mutations in breast cancer driver genes . The promoter of RAD51C was analysed for DNA methylation. RESULTS: A statistically significant excess of loss of function variants were identified in 3080 cases (0.4%) compared with two among 4840 controls (0.04%; odds ratio=8.67, 95% confidence interval=1.89 to 80.52, P<.001) with over half of the carriers having no personal or family history of ovarian cancer. In addition, the association was highly statistically significant among cases with ER negative (P<.001) or triple-negative cancer (P<.001), but not in ER positive cases. Tumor sequencing from carriers confirmed bi-allelic inactivation in all the triple-negative cases and was associated with high HRD scores and mutational signature 3 indicating homologous recombination repair deficiency. CONCLUSION: This study provide evidence that germline loss-of-function variants of RAD51C are associated with hereditary breast cancer, particular triple-negative type. RAD51C-null breast cancers possess similar genomic and clinical features to BRCA1-null cancers and may also be vulnerable to DNA double-strand break inducing chemotherapies and PARP inhibitors.

14.
Nat Commun ; 10(1): 1741, 2019 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-30988301

RESUMO

Genome-wide association studies (GWAS) have identified more than 170 breast cancer susceptibility loci. Here we hypothesize that some risk-associated variants might act in non-breast tissues, specifically adipose tissue and immune cells from blood and spleen. Using expression quantitative trait loci (eQTL) reported in these tissues, we identify 26 previously unreported, likely target genes of overall breast cancer risk variants, and 17 for estrogen receptor (ER)-negative breast cancer, several with a known immune function. We determine the directional effect of gene expression on disease risk measured based on single and multiple eQTL. In addition, using a gene-based test of association that considers eQTL from multiple tissues, we identify seven (and four) regions with variants associated with overall (and ER-negative) breast cancer risk, which were not reported in previous GWAS. Further investigation of the function of the implicated genes in breast and immune cells may provide insights into the etiology of breast cancer.


Assuntos
Neoplasias da Mama/genética , Predisposição Genética para Doença , Feminino , Perfilação da Expressão Gênica , Estudo de Associação Genômica Ampla , Humanos , Locos de Características Quantitativas
15.
Cancer Prev Res (Phila) ; 12(6): 383-390, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31003994

RESUMO

Individualized screening is our logical next step to improve population breast cancer screening in Australia. To explore breast screening participants' views of the current program in Victoria, Australia, examine their openness to change, and attitudes toward an individualized screening model, this qualitative work was performed from a population-based breast screening cohort. This work was designed to inform the development of a decision aid to facilitate women's decisions about participating in individualized screening, and to elicit Australian consumer perspectives on the international movement toward individualized breast screening. A total of 52 women participated in one of four focus groups, and were experienced with screening with 90% of participants having had more than three mammograms. Focus group discussion was facilitated following three main themes: (i) experience of breast screening; (ii) breast cancer risk perception, and (iii) views on individualized screening. Participants had strong, positive, emotional ties to breast screening in its current structure but were supportive, with some reservations, of the idea of individualized screening. There was good understanding about the factors contributing to personalized risk and a wide range of opinions about the inclusion of genetic testing with genetic testing being considered a foreign and evolving domain. Individualized breast screening that takes account of risk factors such as mammographic density, lifestyle, and genetic factors would be acceptable to a population of women who are invested in the current system. The communication and implementation of a new program would be critical to its acceptance and potential success. Reservations may be had in regards to uptake of genetic testing, motivations behind the change, and management of the women allocated to a lower risk category.

16.
Multivariate Behav Res ; 54(1): 147-148, 2019 Jan-Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30931635
17.
Exp Physiol ; 104(6): 920-931, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30919515

RESUMO

NEW FINDINGS: What is the central question of this study? To what extent are the mechanical-ventilatory responses to upper-body exercise influenced by task-specific locomotor mechanics? What is the main finding and its importance? When compared with lower-body exercise performed at similar ventilations, upper-body exercise was characterized by tidal volume constraint, dynamic lung hyperinflation and an increased propensity towards neuromechanical uncoupling of the respiratory system. Importantly, these responses were independent of respiratory dysfunction and flow limitation. Thus, the mechanical ventilatory responses to upper-body exercise are attributable, in part, to task-specific locomotor mechanics (i.e. non-respiratory loading of the thorax). ABSTRACT: The aim of this study was to determine the extent to which the mechanical ventilatory responses to upper-body exercise are influenced by task-specific locomotor mechanics. Eight healthy men (mean ± SD: age, 24 ± 5 years; mass, 74 ± 11 kg; and stature, 1.79 ± 0.07 m) completed two maximal exercise tests, on separate days, comprising 4 min stepwise increments of 15 W during upper-body exercise (arm-cranking) or 30 W during lower-body exercise (leg-cycling). The tests were repeated at work rates calculated to elicit 20, 40, 60, 80 and 100% of the peak ventilation achieved during arm-cranking ( V ̇ E , UBE ). Exercise measures included pulmonary ventilation and gas exchange, oesophageal pressure-derived indices of respiratory mechanics, operating lung volumes and expiratory flow limitation. Subjects exhibited normal resting pulmonary function. Arm-crank exercise elicited significantly lower peak values for work rate, O2 uptake, CO2 output, minute ventilation and tidal volume (p < 0.05). At matched ventilations, arm-crank exercise restricted tidal volume expansion relative to leg-cycling exercise at 60% V ̇ E , UBE (1.74 ± 0.61 versus 2.27 ± 0.68 l, p < 0.001), 80% V ̇ E , UBE (2.07 ± 0.70 versus 2.52 ± 0.67 l, p < 0.001) and 100% V ̇ E , UBE (1.97 ± 0.85 versus 2.55 ± 0.72 l, p = 0.002). Despite minimal evidence of expiratory flow limitation, expiratory reserve volume was significantly higher during arm-cranking versus leg-cycling exercise at 100% V ̇ E , UBE (39 ± 8 versus 29 ± 8% of vital capacity, p = 0.002). At any given ventilation, arm-cranking elicited greater inspiratory effort (oesophageal pressure) relative to thoracic displacement (tidal volume). Arm-cranking exercise is sufficient to provoke respiratory mechanical derangements (restricted tidal volume expansion, dynamic hyperinflation and neuromechanical uncoupling) in subjects with normal pulmonary function and expiratory flow reserve. These responses are likely to be attributable to task-specific locomotor mechanics (i.e. non-respiratory loading of the thorax).

18.
J Pathol ; 248(3): 326-338, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30843206

RESUMO

The current model for breast cancer progression proposes independent 'low grade (LG)-like' and 'high grade (HG)-like' pathways but lacks a known precursor to HG cancer. We applied low-coverage whole-genome sequencing to atypical ductal hyperplasia (ADH) with and without carcinoma to shed light on breast cancer progression. Fourteen out of twenty isolated ADH cases harboured at least one copy number alteration (CNA), but had fewer aberrations than LG or HG ductal carcinoma in situ (DCIS). ADH carried more HG-like CNA than LG DCIS (e.g. 8q gain). Correspondingly, 64% (7/11) of ADH cases with synchronous HG carcinoma were clonally related, similar to LG carcinoma (67%, 6/9). This study represents a significant shift in our understanding of breast cancer progression, with ADH as a common precursor lesion to the independent 'low grade-like' and 'high grade-like' pathways. These data suggest that ADH can be a precursor of HG breast cancer and that LG and HG carcinomas can evolve from a similar ancestor lesion. We propose that although LG DCIS may be committed to a LG molecular pathway, ADH may remain multipotent, progressing to either LG or HG carcinoma. This multipotent nature suggests that some ADH cases could be more clinically significant than LG DCIS, requiring biomarkers for personalising management. Copyright © 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

19.
Lung Cancer ; 129: 1-7, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30797485

RESUMO

OBJECTIVES: To update the prevalence of smoking in people as they were diagnosed with non-small cell lung cancer (NSCLC) and to see whether smoking status at baseline and quitting are independently associated with 1-year survival. DESIGN: A real-world cohort study following patients from diagnosis for up to 1 year or until death. SETTING: UK multi-centre study (28 sites) based in secondary and primary care. PARTICIPANTS: 1124 patients with newly diagnosed NSCLC between 2010-2016. MAIN OUTCOME MEASURES: Smoking status was validated at diagnosis and at every routine and emergency hospital visit. Cancer treatments were offered according to local multi-disciplinary team decisions following UK guidelines and smoking cessation treatments offered according to local practice /availability. Survival analysis and Cox Proportional Hazards Modelling examined the associations of a) smoking at baseline and b) quitting smoking, on survival at 1 year. RESULTS: 77% of never smokers, 60% of ex-smokers and 57% of current smokers, were alive at 1 year (p = 0.01). After adjusting for age, stage, EGOG, surgery and gender, ex smokers (adjusted HR 1.96, 95% CI 1.16-2.31) and current smokers (aHR 2.04, 1.19-3.48) were both more likely to die within one year. 23% of smokers with NSCLC quit within 3 months of diagnosis. At 1 year, 69% of those who quit were alive versus 53% of those who continued to smoke (p < 0.01). After adjusting the risk of dying was lower (aHR 0.75), in those who quit smoking, although this was not statistically significant (p = 0.23). CONCLUSIONS: This is the largest prospective study that validates smoking in NSCLC; it shows a third of people are smoking at the time of diagnosis. Smokers have lower 12-month survival than never and ex -smokers. Quitting smoking was associated with 25% reduction in mortality which may be clinically important although not statistically significant, after adjusting for other factors.

20.
J Pathol ; 248(2): 243-252, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30746706

RESUMO

Breast cancer (BC) diagnosed after a negative mammogram but prior to the next screening episode is termed an 'interval BC' (IBC). Understanding the molecular differences between IBC and screen-detected BCs (SDBC) could improve mammographic screening and management options. Therefore, we assessed both germline and somatic genomic aberrations in a prospective cohort. Utilising the Lifepool cohort of >54 000 women attending mammographic screening programs, 930 BC cases with screening status were identified (726 SDBC and 204 IBC). Clinico-pathological and family history information were recorded. Germline and tumour DNA were collected where available and sequenced for BC predisposition and driver gene mutations. Compared to SDBC, IBCs were significantly associated with a younger age at diagnosis and tumour characteristics associated with worse prognosis. Germline DNA assessment of BC cases that developed post-enrolment (276 SDBCs and 77 IBCs) for pathogenic mutations in 12 hereditary BC predisposition genes identified 8 carriers (2.27%). The germline mutation frequency was higher in IBC versus SDBC, although not statistically significant (3.90% versus 1.81%, p = 0.174). Comparing somatic genetic features of IBC and SDBC matched for grade, histological subtype and hormone receptor revealed no significant differences, with the exception of higher homologous recombination deficiency scores in IBC, and copy number changes on chromosome Xq in triple negative SDBCs. Our data demonstrates that while IBCs are clinically more aggressive than SDBC, when matched for confounding clinico-pathological features they do not represent a unique molecular class of invasive BC, but could be a consequence of timing of tumour initiation and mammographic screening. Copyright © 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

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