Axitinib in patients with advanced/metastatic soft tissue sarcoma (Axi-STS): an open-label, multicentre, phase II trial in four histological strata.

BACKGROUND: Axitinib is an oral vascular endothelial growth factor receptor inhibitor with anti-tumour activity in renal, thyroid, and pancreatic cancer. METHODS: Axi-STS was a pathologically-stratified, non-randomised, open-label, multi-centre, phase II trial of continuous axitinib treatment in patients ≥16 years, performance status ≤2, with pathologically-confirmed advanced/metastatic soft tissue sarcoma (STS). Patients were recruited within four tumour strata, each analysed separately: angiosarcoma, leiomyosarcoma, synovial sarcoma, or other eligible STSs. The primary outcome was progression-free survival at 12 weeks (PFS12). A Simon's two-stage design with activity defined as PFS12 rate of 40% determined a sample size of 33 patients per strata. RESULTS: Between 31-August-2010 and 29-January-2016, 145 patients were recruited: 38 angiosarcoma, 37 leiomyosarcoma, 36 synovial sarcoma, and 34 other subtypes. PFS12 rate for each stratum analysed was 42% (95% lower confidence interval (LCI); 29), 45% (95% LCI; 32), 57% (95% LCI; 42), and 33% (95% LCI; 21), respectively. There were 74 serious adverse events including two treatment-related deaths of pulmonary haemorrhage and gastrointestinal bleeding. Fatigue and hypertension were the most common grade 3 adverse events. CONCLUSIONS: Axitinib showed clinical activity in all STS strata investigated. The adverse event profile was acceptable, supporting further investigation in phase III trials. CLINICAL TRIAL REGISTRATION: ISRCTN 60791336.

Emerging Role of Artificial Intelligence and Big Data in Spine Care.

The pace of US Food and Drug Administration-approved medical devices that incorporate artificial intelligence (AI) or machine learning as part of the device is accelerating. As of September 2021, 350 such devices have been approved for commercial sale in the United States. As much as AI has become ubiquitous in our lives-keeping our cars between the lines on the highway, converting speech to text on the fly, recommending movies, books, or restaurants, and so much more, AI also appears destined to become a routine aspect in daily spine surgery. Neural network types of AI programs have achieved extraordinary pattern recognition and predictive abilities-far surpassing human capabilities-and thus appears well suited to back pain and spine surgery diagnostic and treatment pattern recognition and prediction tasks. These AI programs are also data hungry. As luck would have it, surgery generates an estimated 80 MB per patient per day collected in a variety of datasets. When aggregated, this represents a 200+ billion patient record data ocean of diagnostic and treatment patterns. Such Big Data, when combined with a new generation of convolutional neural network (CNN) AI, set the stage for a cognitive revolution in spine surgery. However, there are important issues and concerns. Spine surgery is a mission-critical task. Because AI programs lack explainability and are absolutely reliant on correlative, not causative, data relationships, the emerging role of AI and Big Data in spine surgery will likely come first in productivity tools and later in narrowly defined spine surgery tasks. The purpose of this article is to review the emergence of AI in spine surgery applications and examine spine surgery heuristics and "expert" decision models within the context of AI and Big Data.

Participatory development of a 3D telemedicine system during COVID: The future of remote consultations.

BACKGROUND: The COVID pandemic brought the need for more realistic remote consultations into focus. 2D Telemedicine solutions fail to replicate the fluency or authenticity of in-person consultations. This research reports on an international collaboration on the participatory development and first validated clinical use of a novel, real-time 360-degree 3D Telemedicine system worldwide. The development of the system - leveraging Microsoft's Holoportation™ communication technology - commenced at the Canniesburn Plastic Surgery Unit, Glasgow, in March 2020. METHODS: The research followed the VR CORE guidelines on the development of digital health trials, placing patients at the heart of the development process. This consisted of three separate studies - a clinician feedback study (23 clinicians, Nov-Dec 2020), a patient feedback study (26 patients, Jul-Oct 2021), and a cohort study focusing on safety and reliability (40 patients, Oct 2021-Mar 2022). "Lose, Keep, and Change" feedback prompts were used to engage patients in the development process and guide incremental improvements. RESULTS: Participatory testing demonstrated improved patient metrics with 3D in comparison to 2D Telemedicine, including validated measures of satisfaction (p<0.0001), realism or 'presence' (Single Item Presence scale, p<0.0001), and quality (Telehealth Usability Questionnaire, p = 0.0002). The safety and clinical concordance (95%) of 3D Telemedicine with a face-to-face consultation were equivalent or exceeded estimates for 2D Telemedicine. CONCLUSIONS: One of the ultimate goals of telemedicine is for the quality of remote consultations to get closer to the experience of face-to-face consultations. These data provide the first evidence that Holoportation™ communication technology brings 3D Telemedicine closer to this goal than a 2D equivalent.

Early Dietary Exposures Epigenetically Program Mammary Cancer Susceptibility through Igf1-Mediated Expansion of the Mammary Stem Cell Compartment.

Diet is a critical environmental factor affecting breast cancer risk, and recent evidence shows that dietary exposures during early development can affect lifetime mammary cancer susceptibility. To elucidate the underlying mechanisms, we used our established crossover feeding mouse model, where exposure to a high-fat and high-sugar (HFHS) diet during defined developmental windows determines mammary tumor incidence and latency in carcinogen-treated mice. Mammary tumor incidence is significantly increased in mice receiving a HFHS post-weaning diet (high-tumor mice, HT) compared to those receiving a HFHS diet during gestation (low-tumor mice, LT). The current study revealed that the mammary stem cell (MaSC) population was significantly increased in mammary glands from HT compared to LT mice. Igf1 expression was increased in mammary stromal cells from HT mice, where it promoted MaSC self-renewal. The increased Igf1 expression was induced by DNA hypomethylation of the Igf1 Pr1 promoter, mediated by a decrease in Dnmt3b levels. Mammary tissues from HT mice also had reduced levels of Igfbp5, leading to increased bioavailability of tissue Igf1. This study provides novel insights into how early dietary exposures program mammary cancer risk, demonstrating that effective dietary intervention can reduce mammary cancer incidence.

Overexpression of IGF-1 During Early Development Expands the Number of Mammary Stem Cells and Primes them for Transformation.

Insulin-like growth factor I (IGF-1) has been implicated in breast cancer due to its mitogenic and anti-apoptotic effects. Despite substantial research on the role of IGF-1 in tumor progression, the relationship of IGF-1 to tissue stem cells, particularly in mammary tissue, and the resulting tumor susceptibility has not been elucidated. Previous studies with the BK5.IGF-1 transgenic (Tg) mouse model reveals that IGF-1 does not act as a classical, post-carcinogen tumor promoter in the mammary gland. Pre-pubertal Tg mammary glands display increased numbers and enlarged sizes of terminal end buds, a niche for mammary stem cells (MaSCs). Here we show that MaSCs from both wild-type (WT) and Tg mice expressed IGF-1R and that overexpression of Tg IGF-1 increased numbers of MaSCs by undergoing symmetric division, resulting in an expansion of the MaSC and luminal progenitor (LP) compartments in pre-pubertal female mice. This expansion was maintained post-pubertally and validated by mammosphere assays in vitro and transplantation assays in vivo. The addition of recombinant IGF-1 promoted, and IGF-1R downstream inhibitors decreased mammosphere formation. Single-cell transcriptomic profiles generated from 2 related platforms reveal that IGF-1 stimulated quiescent MaSCs to enter the cell cycle and increased their expression of genes involved in proliferation, plasticity, tumorigenesis, invasion, and metastasis. This study identifies a novel, pro-tumorigenic mechanism, where IGF-1 increases the number of transformation-susceptible carcinogen targets during the early stages of mammary tissue development, and "primes" their gene expression profiles for transformation.

CONCORDE: A phase I platform study of novel agents in combination with conventional radiotherapy in non-small-cell lung cancer.

Lung cancer is the leading cause of cancer mortality worldwide and most patients are unsuitable for 'gold standard' treatment, which is concurrent chemoradiotherapy. CONCORDE is a platform study seeking to establish the toxicity profiles of multiple novel radiosensitisers targeting DNA repair proteins in patients treated with sequential chemoradiotherapy. Time-to-event continual reassessment will facilitate efficient dose-finding.

The care of older cancer patients in the United Kingdom.

The ageing population poses new challenges globally. Cancer care for older patients is one of these challenges, and it has a significant impact on societies. In the United Kingdom (UK), as the number of older cancer patients increases, the management of this group has become part of daily practice for most oncology teams in every geographical area. Older cancer patients are at a higher risk of both under- and over-treatment. Therefore, the assessment of a patient's biological age and effective organ functional reserve becomes paramount. This may then guide treatment decisions by better estimating a prognosis and the risk-to-benefit ratio of a given therapy to anticipate and mitigate against potential toxicities/difficulties. Moreover, older cancer patients are often affected by geriatric syndromes and other issues that impact their overall health, function and quality of life. Comprehensive geriatric assessments offer an opportunity to identify and address health problems which may then optimise one's fitness and well-being. Whilst it is widely accepted that older cancer patients may benefit from such an approach, resources are often scarce, and access to dedicated services and research remains limited to specific centres across the UK. The aim of this project is to map the current services and projects in the UK to learn from each other and shape the future direction of care of older patients with cancer.

The sarcoma diagnostic interval: a systematic review on length, contributing factors and patient outcomes.

Sarcomas are rare and heterogeneous mesenchymal tumours of soft tissue or bone, making them prone to late diagnosis. In other malignancies, early diagnosis has an impact on stage of disease, complexity of therapeutic procedures, survival and health-related quality of life (HRQoL). Little is known about what length of diagnostic interval should be considered as delay in patients with bone (BS) or soft tissue sarcomas (STS). To quantify total interval (defined as time from first symptom to histological diagnosis) and its components, identify contributing factors to its length and determine the impact on patients' outcome in terms of mortality and HRQoL. A systematic review was conducted according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Seventy-six articles out of 2310 met the predefined inclusion criteria. Total intervals, varied broadly; 9-120.4 weeks for BS and 4.3-614.9 weeks for STS. Older age and no initial radiological examinations were contributing factors for a long interval in BS, while in STS results were conflicting. The impact of length of total interval on clinical outcomes in terms of survival and morbidity remains ambiguous; no clear relation could be identified for both BS and STS. No study examined the impact on HRQoL. The length of total interval is variable in BS as well as STS. Its effect on outcomes is contradictory. There is no definition of a clinically relevant cut-off point that discriminates between a short or long total interval. Prospero: CRD42017062492.

Meta-analysis of up to 622,409 individuals identifies 40 novel smoking behaviour associated genetic loci.

Smoking is a major heritable and modifiable risk factor for many diseases, including cancer, common respiratory disorders and cardiovascular diseases. Fourteen genetic loci have previously been associated with smoking behaviour-related traits. We tested up to 235,116 single nucleotide variants (SNVs) on the exome-array for association with smoking initiation, cigarettes per day, pack-years, and smoking cessation in a fixed effects meta-analysis of up to 61 studies (up to 346,813 participants). In a subset of 112,811 participants, a further one million SNVs were also genotyped and tested for association with the four smoking behaviour traits. SNV-trait associations with P < 5 × 10-8 in either analysis were taken forward for replication in up to 275,596 independent participants from UK Biobank. Lastly, a meta-analysis of the discovery and replication studies was performed. Sixteen SNVs were associated with at least one of the smoking behaviour traits (P < 5 × 10-8) in the discovery samples. Ten novel SNVs, including rs12616219 near TMEM182, were followed-up and five of them (rs462779 in REV3L, rs12780116 in CNNM2, rs1190736 in GPR101, rs11539157 in PJA1, and rs12616219 near TMEM182) replicated at a Bonferroni significance threshold (P < 4.5 × 10-3) with consistent direction of effect. A further 35 SNVs were associated with smoking behaviour traits in the discovery plus replication meta-analysis (up to 622,409 participants) including a rare SNV, rs150493199, in CCDC141 and two low-frequency SNVs in CEP350 and HDGFRP2. Functional follow-up implied that decreased expression of REV3L may lower the probability of smoking initiation. The novel loci will facilitate understanding the genetic aetiology of smoking behaviour and may lead to the identification of potential drug targets for smoking prevention and/or cessation.

Management strategies and 5-year outcomes in Polish patients with stable coronary artery disease versus other European countries: data from the CLARIFY registry.

INTRODUCTION An international registry of ambulatory patients with stable coronary artery disease (CLARIFY) allows a comparison of management and outcomes in real­life setting. OBJECTIVES We aimed to compare the management strategies and 5­year outcomes in patients from Poland and from other European countries. PATIENTS AND METHODS Stable coronary artery disease was defined as previous myocardial infarction (MI) or revascularization, coronary stenosis greater than 50%, or documented symptomatic myocardial ischemia. Patients were followed on an annual basis for 5 years. RESULTS Among the total of 32 703 patients, 1000 were enrolled in Poland, and 17 326 in other European countries. Polish patients were younger, with a higher proportion of women, smokers, and patients with previous MI, dyslipidemia, and hypertension. Patients in both cohorts received adequate medical treatment, with more Polish patients receiving ß­blockers. Blood pressure and lipid control to target was similar and remained low in both cohorts. Diabetes control and successful smoking cessation rates were lower in Poland than in other European countries. Polish patients more often underwent percutaneous coronary intervention. All­cause (8.5% vs 7.9%; P = 0.81) and cardiovascular death rates (5.3% vs 4.9%; P = 0.82) did not differ between the groups, but fatal or nonfatal MI occurred more often in the Polish cohort (5% vs 3.1%; P = 0.006). Angina control was better in Poland than in other European countries (Canadian Cardiovascular Society class II-IV, 11.5% vs 15.8% of patients; P <0.001). CONCLUSIONS Risk factor control was insufficient both in patients from Poland and in those from other European countries. The more frequent use of revascularization in Polish patients was not linked to improved outcomes, but, together with more extensive prescription of ß­blockers, might have contributed to better angina control.

The Influence of Socio-economic Deprivation on Mobility, Participation, and Quality of Life Following Major Lower Extremity Amputation in the West of Scotland.

OBJECTIVE: Lower extremity amputation (LEA) is more common in people from lower socio-economic groups. This study examined this further by investigating the influence of socio-economic status on mobility, participation, and quality of life (QoL) after LEA. METHODS: Prospective data were gathered for all LEAs performed in one year in one Scottish Health Board, commencing March 2014. A postcode derived Scottish Index of Multiple Deprivation (SIMD) was applied by quintile (SIMD 1 = most deprived). Routine data were collected on the cohort of 171 patients; 101 participants consented and received postal questionnaires on QoL (EQ-5D-5L), participation (Reintegration to Normal Living Index [RNLI]), and mobility (Prosthetic Limb User Survey of Mobility), six (n = 67) and 12 months (n = 50) after LEA. RESULTS: The mean ± SD age of the cohort was 66.2 ± 11.4 years; 75% were male and 53% had diabetes. In total, 67% lived in SIMD 1 and 2 and 11.1% in SIMD 5. Sixty per cent had a transtibial amputation. Mortality was 6% at 30 days 17% at six, and 29% at 12 months. Those in SIMD 1 were significantly younger (62.9 years) than those in SIMD 5 (76.3 years). Significantly more participants with a transfemoral amputation (TFA) lived in SIMD 1 (44%) compared with SIMD 5 (11%) (p = .004). Participation was low (RNLI scores: 6 months = 55.7; 12 months = 56.6) and PLUS M scores suggested mobility was poor overall at six (39.1) and 12 months (38.9). Mean QoL was 0.37 at 6 months and 0.33 at 12 months. CONCLUSION: Although this study observed more LEAs in those from low socio-economic areas, it is impossible to conclude whether QoL after LEA is truly influenced by socio-economic status. There was an association between the disproportionately high rate of LEAs in SIMD groups 1 and 2 and the high prevalence of smoking, 61% vs. only 21% of those in the least deprived areas (SIMD 3, 4, and 5) being current smokers.

Impact of Concomitant Administration of Gastric Acid-Suppressive Agents and Pazopanib on Outcomes in Soft-Tissue Sarcoma Patients Treated within the EORTC 62043/62072 Trials.

PURPOSE: Pazopanib is active in soft-tissue sarcoma (STS). Because pazopanib absorption is pH-dependent, coadministration with gastric acid-suppressive (GAS) agents such as proton pump inhibitors could affect exposure of pazopanib, and thereby its therapeutic effects. PATIENTS AND METHODS: The EORTC 62043 and 62072 were single-arm phase II and placebo-controlled phase III studies, respectively, of pazopanib in advanced STS. We first compared the outcome of patients treated with pazopanib with or without GAS agents for ≥80% of treatment duration, and subsequently using various thresholds. The impact of concomitant GAS therapy was assessed on progression-free survival (PFS) and overall survival (OS) using multivariate Cox models, exploring and comparing also the potential effect on placebo-treated patients. RESULTS: Of 333 eligible patients, 59 (17.7%) received concomitant GAS therapy for >80% of pazopanib treatment duration. Median PFS was shorter in GAS therapy users versus nonusers: 2.8 vs. 4.6 months, respectively [HR, 1.49; 95% confidence interval (CI), 1.11-1.99; P = 0.01]. Concomitant administration of GAS therapy was also associated with a shorter median OS: 8.0 vs. 12.6 months (HR, 1.81; 95% CI, 1.31-2.49; P < 0.01). The longer the overlapping use of GAS agents and pazopanib, the worse the outcome with pazopanib. These effects were not observed in placebo-treated patients (HR, 0.82; 95% CI, 0.51-1.34; P = 0.43 for PFS and HR, 0.84; 95% CI, 0.48-1.48; P = 0.54 for OS). CONCLUSIONS: Coadministration of long-term GAS therapy with pazopanib was associated with significantly shortened PFS and OS. Withdrawal of GAS agents must be considered whenever possible. Therapeutic drug monitoring of pazopanib plasma concentrations may be helpful for patients on pazopanib and GAS therapy.

Dynamic role of the codon 72 p53 single-nucleotide polymorphism in mammary tumorigenesis in a humanized mouse model.

Female breast cancer (BrCa) is the most common noncutaneous cancer among women in the United States. Human epidemiological studies reveal that a p53 single-nucleotide polymorphism (SNP) at codon 72, encoding proline (P72) or arginine (R72), is associated with differential risk of several cancers, including BrCa. However, the molecular mechanisms by which these variants affect mammary tumorigenesis remain unresolved. To investigate the effects of this polymorphism on susceptibility to mammary cancer, we used a humanized p53 mouse model, homozygous for either P72 or R72. Our studies revealed that R72 mice had a significantly higher mammary tumor incidence and reduced latency in both DMBA-induced and MMTV-Erbb2/Neu mouse mammary tumor models compared to P72 mice. Analyses showed that susceptible mammary glands from E-R72 (R72 x MMTV-Erbb2/Neu) mice developed a senescence-associated secretory phenotype (SASP) with influx of proinflammatory macrophages, ultimately resulting in chronic, protumorigenic inflammation. Mammary tumors arising in E-R72 mice also had an increased influx of tumor-associated macrophages, contributing to angiogenesis and elevated tumor growth rates. These results demonstrate that the p53 R72 variant increased susceptibility to mammary tumorigenesis through chronic inflammation.

Anti-angiogenic therapies for the treatment of angiosarcoma: a clinical update.

Angiosarcomas are rare aggressive endothelial tumours, and are associated with a poor prognosis. Due to their vascular nature, there is great interest in their response to anti-angiogenic agents. A number of small prospective studies have reported angiosarcoma response to vascular-targeted agents, including agents that target vascular endothelial growth factor. To date, the response to these agents has been disappointing, and similar to the response observed in other soft tissue sarcoma subtypes. This short review will summarise the recent data in this field.

Management and clinical outcome of stable coronary artery disease in Austria : Results from 5 years of the CLARIFY registry.

BACKGROUND: The population of patients with established coronary artery disease (CAD) is growing because of an improvement in outcomes and survival from acute disease episodes. Nevertheless, these patients remain at high risk of cardiovascular events. Thus, CAD management is important in prevention of disease progression. The objective of this analysis was to describe disease management and clinical outcome of Austrian outpatients with stable CAD over 5 years by using data from the international CLARIFY registry. METHODS: CLARIFY was an international prospective observational registry of outpatients with stable CAD, defined as prior myocardial infarction or revascularization (CABG or PCI), coronary stenosis of more than 50% by coronary angiography or chest pain with myocardial ischemia. We analyzed demographic characteristics, risk factors, treatments and clinical outcomes of 424 Austrian outpatients with established CAD who were enrolled between November 2009 and July 2010 and observed until September 2015. RESULTS: The primary risk factors in Austrian outpatients with stable CAD were smoking (current smokers: 13.2%), overweight (77.1%), hypertension (78.5%), raised low-density lipoprotein (LDL) cholesterol plasma levels (81.4% ≥ 0.7 g/l or 1.8 mmol/l), elevated heart rate (≥70 bpm: 60.9% in patients with anginal symptoms) and poor physical activity (none or light activity: 63.4%). Patients received lipid-lowering drugs (predominantly statins), aspirin, beta-blockers and angiotensin-converting enzyme (ACE) inhibitors according to current recommendations. After 5 years a systolic blood pressure (SBP) < 140 mm Hg and diastolic blood pressure (DBP) < 90 mm Hg was reached in 58.5% of patients. Of the patients 70.4% had LDL cholesterol plasma levels below 1.0 g/l (2.6 mmol/l), 42.1% of smokers had stopped smoking, 42.9% of patients with anginal symptoms had a heart rate ≤60 bpm and 26.0% of diabetic patients had brought their HbA1c levels below 6.5%. Cardiovascular death, myocardial infarction or stroke occurred in 30 patients (7.1%), all-cause death in 25 cases (5.9%) and cardiovascular death in 15 cases (3.5%). Myocardial infarction was reported in 14 patients (fatal and non-fatal: 3.3%) and stroke in 8 patients (fatal and non-fatal: 1.9%), 39 patients (9.2%) underwent myocardial revascularization and 124 patients (29.2%) experienced cardiovascular hospitalization. CONCLUSION: Characteristics of Austrian outpatients with stable CAD corresponded to those of patients with CAD in other developed countries. Medical treatments following the recommendations of the European guidelines were prescribed in the majority of patients; however, recommended goals of life style interventions including a heart rate less than 60 bpm and general risk factor management were not achieved by a high proportion of patients. Heart rate control and life style changes remain unmet needs of cardiovascular care in Austria.

Early Exposure to a High Fat/High Sugar Diet Increases the Mammary Stem Cell Compartment and Mammary Tumor Risk in Female Mice.

Obesity and alterations in metabolic programming from early diet exposures can affect the propensity to disease in later life. Through dietary manipulation, developing mouse pups were exposed to a hyperinsulinemic, hyperglycemic milieu during three developmental phases: gestation, lactation, and postweaning. Analyses showed that a postweaning high fat/high sugar (HF/HS) diet had the main negative effect on adult body weight, glucose tolerance, and insulin resistance. However, dimethylbenz[a]anthracene (DMBA)-induced carcinogenesis revealed that animals born to a mother fed a HF/HS gestation diet, nursed by a mother on a mildly diet-restricted, low fat/low sugar diet (DR) and weaned onto a HF/HS diet (HF/DR/HF) had the highest mammary tumor incidence, while HF/HF/DR had the lowest tumor incidence. Cox proportional hazards analysis showed that a HF/HS postweaning diet doubled mammary cancer risk, and a HF/HS diet during gestation and postweaning increased risk 5.5 times. Exposure to a HF/HS diet during gestation, when combined with a postweaning DR diet, had a protective effect, reducing mammary tumor risk by 86% (HR = 0.142). Serum adipocytokine analysis revealed significant diet-dependent differences in leptin/adiponectin ratio and IGF-1. Flow cytometry analysis of cells isolated from mammary glands from a high tumor incidence group, DR/HF/HF, showed a significant increase in the size of the mammary stem cell compartment compared with a low tumor group, HF/HF/DR. These results indicate that dietary reprogramming induces an expansion of the mammary stem cell compartment during mammary development, increasing likely carcinogen targets and mammary cancer risk. Cancer Prev Res; 10(10); 553-62. ©2017 AACRSee related editorial by Freedland, p. 551-2.

Loss of Cardioprotective Effects at the ADAMTS7 Locus as a Result of Gene-Smoking Interactions.

BACKGROUND: Common diseases such as coronary heart disease (CHD) are complex in etiology. The interaction of genetic susceptibility with lifestyle factors may play a prominent role. However, gene-lifestyle interactions for CHD have been difficult to identify. Here, we investigate interaction of smoking behavior, a potent lifestyle factor, with genotypes that have been shown to associate with CHD risk. METHODS: We analyzed data on 60 919 CHD cases and 80 243 controls from 29 studies for gene-smoking interactions for genetic variants at 45 loci previously reported to be associated with CHD risk. We also studied 5 loci associated with smoking behavior. Study-specific gene-smoking interaction effects were calculated and pooled using fixed-effects meta-analyses. Interaction analyses were declared to be significant at a P value of <1.0×10-3 (Bonferroni correction for 50 tests). RESULTS: We identified novel gene-smoking interaction for a variant upstream of the ADAMTS7 gene. Every T allele of rs7178051 was associated with lower CHD risk by 12% in never-smokers (P=1.3×10-16) in comparison with 5% in ever-smokers (P=2.5×10-4), translating to a 60% loss of CHD protection conferred by this allelic variation in people who smoked tobacco (interaction P value=8.7×10-5). The protective T allele at rs7178051 was also associated with reduced ADAMTS7 expression in human aortic endothelial cells and lymphoblastoid cell lines. Exposure of human coronary artery smooth muscle cells to cigarette smoke extract led to induction of ADAMTS7. CONCLUSIONS: Allelic variation at rs7178051 that associates with reduced ADAMTS7 expression confers stronger CHD protection in never-smokers than in ever-smokers. Increased vascular ADAMTS7 expression may contribute to the loss of CHD protection in smokers.

Predictive and prognostic factors associated with soft tissue sarcoma response to chemotherapy: a subgroup analysis of the European Organisation for Research and Treatment of Cancer 62012 study.

BACKGROUND: The European Organization for Research and Treatment of Cancer (EORTC) 62012 study was a Phase III trial of doxorubicin versus doxorubicin-ifosfamide chemotherapy in 455 patients with advanced soft tissue sarcoma (STS). Analysis of the main study showed that combination chemotherapy improved tumor response and progression-free survival, but differences in overall survival (OS) were not statistically significant. We analyzed factors prognostic for tumor response and OS, and assessed histological subgroup and tumor grade as predictive factors to identify patients more likely to benefit from combination chemotherapy. METHODS: Central pathology review was performed by six reference pathologists. Gender, age, performance status, time from first presentation with sarcoma to starting palliative chemotherapy, tumor grade, histological subgroup, primary tumor site involvement, and sites of metastases were assessed as prognostic factors. RESULTS: Three hundred and ten patients were included in this study. Discordance between local and central pathology opinion of tumor histology and tumor grade was observed in 98 (32%) and 122 (39%) cases, respectively. In multivariate analysis, liposarcoma patients had improved tumor response compared to other histological subgroups, whilst patients with metastases other than lung, liver or bone had a poorer response [odds ratio (OR) 0.42, 95% confidence interval (CI) 0.23-0.78; p = 0.006]. Patients with bone metastases had reduced OS [hazard ratio (HR) 1.56, 95% CI 1.16-2.09; p = 0.003]. By central pathology review, patients with undifferentiated pleomorphic sarcoma (UPS) had improved tumor response and OS with doxorubicin-ifosfamide compared to single-agent doxorubicin (OR 9.90, 95% CI 1.93-50.7 and HR 0.44, 95% CI 0.26-0.79, respectively). Grade III tumors had improved response with combination chemotherapy but there was no interaction between chemotherapy and grade on OS. CONCLUSIONS: Prospective central pathology review of tumor histology should be integrated into future STS clinical trials. Doxorubicin-ifosfamide may be most appropriate for young, fit patients with poorly differentiated Grade III tumors including UPS.

Efficacy of eribulin in breast cancer: a short report on the emerging new data.

Eribulin is a novel microtubule-targeting agent that is approved for the treatment of patients with locally advanced or metastatic breast cancer who have previously received treatment with an anthracycline and a taxane in either the adjuvant or metastatic setting. Eribulin induces mitotic catastrophe leading to cell death but has other important antitumor effects, including reversal of epithelial-mesenchymal transition and remodeling of the tumor vasculature. Eribulin was licensed for the treatment of advanced breast cancer based on results from two large randomized Phase III clinical trials. Current clinical trials of eribulin for breast cancer are evaluating response to treatment earlier in the patient pathway and in combination with other therapeutic agents. This review provides a short overview of emerging new data on the mode of action of eribulin in breast cancer.