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Pathogenic germline exonuclease domain (ED) variants of POLE and POLD1 cause the Mendelian dominant condition polymerase proof-reading associated polyposis (PPAP). We aimed to describe the clinical features of all PPAP patients with probably pathogenic variants. We identified patients with a variants mapping to the EDs of POLE or POLD1 from cancer genetics clinics, a colorectal cancer (CRC) clinical trial, and systematic review of the literature. We used multiple evidence sources to separate ED variants into those with strong evidence of pathogenicity and those of uncertain importance. We performed quantitative analysis of the risk of CRC, colorectal adenomas, endometrial cancer or any cancer in the former group. 132 individuals carried a probably pathogenic ED variant (105 POLE, 27 POLD1). The earliest malignancy was colorectal cancer at 14. The most common tumour types were colorectal, followed by endometrial in POLD1 heterozygotes and duodenal in POLE heterozygotes. POLD1-mutant cases were at a significantly higher risk of endometrial cancer than POLE heterozygotes. Five individuals with a POLE pathogenic variant, but none with a POLD1 pathogenic variant, developed ovarian cancer. Nine patients with POLE pathogenic variants and one with a POLD1 pathogenic variant developed brain tumours. Our data provide important evidence for PPAP management. Colonoscopic surveillance is recommended from age 14 and upper-gastrointestinal surveillance from age 25. The management of other tumour risks remains uncertain, but surveillance should be considered. In the absence of strong genotype–phenotype associations, these recommendations should apply to all PPAP patients.

Introduction and objectives: Coronary lesions with stent overlapping are associated with higher neointimal proliferation that leads to more restenosis. Furthermore, the tapering of coronary arteries is a major challenge when treating long coronary lesions. This study attempted to assess the safety and clinical level of performance of long nontapered sirolimus-eluting coronary stent systems (> 36 mm) to treat long and diffused de novo coronary lesions in real-world scenarios. Methods: This was a prospective, non-randomized, multicentre study that included 696 consecutive patients treated with the long nontapered BioMime sirolimus-eluting coronary stent system in long and diffused de novo coronary lesions. The safety endpoint was major adverse cardiovascular events defined as a composite of cardiac death, myocardial infarction, clinically driven target lesion revascularization, stent thrombosis, and major bleeding at the 12-month follow-up. Results: Of a total of 696 patients, 38.79% were diabetic. The mean age of all the patients was 64.6 ± 14 years, and 80% were males. The indication for revascularization was acute coronary syndrome in 63.1%. A total of 899 lesions were identified out of which 742 were successfully treated with long BioMime stents (37 mm, 40 mm, 44 mm, and 48 mm). The cumulative incidence of major adverse cardiovascular events was 8.1% at the 12-month follow-up including cardiac death (2.09%), myocardial infarction (1.34%), and total stent thrombosis (0.5%). Conclusions: This study confirms the safety and good performance of long nontapered BioMime coronary stents to treat de novo coronary stenosis. Therefore, it can be considered a safe and effective treatment for long and diffused de novo coronary lesions in the routine clinical practice.

The genomic drivers of immune exclusion in colorectal cancer liver metastases (CRCLM) remain poorly understood. Chromosomal instability (CIN), resulting in aneuploidy and genomic rearrangements, is the central pathway of mismatch repair-proficient colorectal cancer pathogenesis; however, it is unknown whether CIN impacts the outcomes of patients with limited spread of CRCLM treated with curative intent cytotoxic chemotherapy and surgery. Herein, we examined the relationship between CIN and the molecular subtypes of CRCLM, immune signaling, treatment sensitivity, and patient outcomes in three independent CRCLM patient cohorts. We established that a previously developed 70-gene CIN signature (CIN70) is a reliable measure of CIN, encompassing features of both aneuploidy and cellular proliferation. We demonstrated that tumors with the canonical subtype of CRCLM exhibit elevated levels of CIN and aneuploidy. Genomically unstable tumors were associated with an immune-depleted tumor microenvironment, and patients with genomically unstable tumors were at increased risk for disease progression in adverse metastatic sites, resulting in poor progression-free and overall survival. However, high-CIN tumors were particularly susceptible to DNA-damaging chemotherapies, including topoisomerase inhibitors, as well as radiation therapy. Treatment with genotoxic agents depleted CIN-rich cell populations, which resulted in a concomitant increase in intratumoral CD8+ T-cells in patients with primary rectal, breast, and bladder cancer. Taken together, we propose a mechanistic explanation for why cytotoxic chemotherapy can augment anti-tumor immunity and improve outcomes in patients with genomically unstable cancers.

Aims: After local excision of early rectal cancer, definitive lymph node status is not available. An alternative means for accurate assessment of recurrence risk is required to determine the most appropriate subsequent management. Currently used measures are suboptimal. We assess three measures of tumour stromal content to determine their predictive value after local excision in a well-characterised cohort of rectal cancer patients without prior radiotherapy. Methods and results: A total of 143 patients were included. Haematoxylin and eosin (H&E) sections were scanned for (i) deep neural network (DNN, a machine-learning algorithm) tumour segmentation into compartments including desmoplastic stroma and inflamed stroma; and (ii) digital assessment of tumour stromal fraction (TSR) and optical DNA ploidy analysis. 3′ mRNA sequencing was performed to obtain gene expression data from which stromal and immune scores were calculated using the ESTIMATE method. Full results were available for 139 samples and compared with disease-free survival. All three methods were prognostic. Most strongly predictive was a DNN-determined ratio of desmoplastic to inflamed stroma >5.41 (P < 0.0001). A ratio of ESTIMATE stromal to immune score 36.5% (P = 0.037). Conclusions: The DNN-determined ratio of desmoplastic to inflamed ratio is a novel and powerful predictor of disease recurrence in locally excised early rectal cancer. It can be assessed on a single H&E section, so could be applied in routine clinical practice to improve the prognostic information available to patients and clinicians to inform the decision concerning further management.

BackgroundPulmonary arterial (PA) stiffness has an essential contribution to the right ventricular (RV) failure pathogenesis. A comprehensive and multiparameter risk assessment allows predicting mortality and guiding treatment decisions in PA hypertension (PAH). We characterize PA remodeling with intravascular ultrasound (IVUS) in prevalent and stable patients with PAH according to the ESC/ERS risk table and analyze the RV-PA coupling consequences.MethodsTen control subjects and 20 prevalent PAH adult patients underwent right heart catheterization (RHC) with simultaneous IVUS study. We estimated cardiac index (CI), pulmonary vascular resistance, and compliance (PVR, PAC) by standard formulas. From IVUS and RHC data, PA diameter, wall thickness/luminal diameter ratio, and indexes of stiffness (pulsatility, compliance, distensibility, incremental elastic modulus - Einc-, and the stiffness index β) were measured. We evaluated RV-PA coupling by the ratio of tricuspid annular plane systolic excursion to systolic pulmonary arterial pressure (TAPSE/sPAP). The individual average risk was calculated by assigning a score of 1 (low-risk -LR-), 2 (intermediate-risk -IR-), and 3 (high-risk -HR-) for each of seven variables (functional class, six-minute walking test, brain natriuretic peptide, right atrial area and pressure, CI, and PA oxygen saturation) and rounding the average value to the nearest integer.ResultsAll PA segments interrogated showed increased vessel diameter, wall cross-sectional area (WCSA), and stiffness in patients with PAH compared to control subjects. 45% corresponded to LR, and 55% corresponded to IR PAH patients. The different measurements of PA stiffness showed significant correlations with TAPSE/sPAP (r = 0.6 to 0.76) in PAH patients. The IR group had higher PA stiffness and lower relative WCSA than LR patients (P < 0.05), and it is associated with a lower PAC and TAPSE/sPAP (P < 0.05).ConclusionIn prevalent PAH patients, the severity of proximal PA remodeling is related to the risk stratification and associated with PAC and RV-PA coupling impairment beyond the indirect effect of the mean PA pressure. The concomitant assessment of IVUS and hemodynamic parameters at diagnosis and follow-up of PAH patients could be a feasible and safe tool for risk stratification and treatment response of the PA vasculopathy during serial hemodynamic measurements.

Objective Complex phenotypes captured on histological slides represent the biological processes at play in individual cancers, but the link to underlying molecular classification has not been clarified or systematised. In colorectal cancer (CRC), histological grading is a poor predictor of disease progression, and consensus molecular subtypes (CMSs) cannot be distinguished without gene expression profiling. We hypothesise that image analysis is a cost-effective tool to associate complex features of tissue organisation with molecular and outcome data and to resolve unclassifiable or heterogeneous cases. In this study, we present an image-based approach to predict CRC CMS from standard H&E sections using deep learning. Design Training and evaluation of a neural network were performed using a total of n=1206 tissue sections with comprehensive multi-omic data from three independent datasets (training on FOCUS trial, n=278 patients; test on rectal cancer biopsies, GRAMPIAN cohort, n=144 patients; and The Cancer Genome Atlas (TCGA), n=430 patients). Ground truth CMS calls were ascertained by matching random forest and single sample predictions from CMS classifier. Results Image-based CMS (imCMS) accurately classified slides in unseen datasets from TCGA (n=431 slides, AUC)=0.84) and rectal cancer biopsies (n=265 slides, AUC=0.85). imCMS spatially resolved intratumoural heterogeneity and provided secondary calls correlating with bioinformatic prediction from molecular data. imCMS classified samples previously unclassifiable by RNA expression profiling, reproduced the expected correlations with genomic and epigenetic alterations and showed similar prognostic associations as transcriptomic CMS. Conclusion This study shows that a prediction of RNA expression classifiers can be made from H&E images, opening the door to simple, cheap and reliable biological stratification within routine workflows.

Background The relation between STEMI and air pollution (AP) is scant. We aimed to investigate the short term association between AP and the incidence of STEMI, and STEMI-related ventricular arrhythmias (VA) and mortality. Methods The study was carried out in the area of Barcelona from January 2010 to December 2011. Daily STEMI rates and incidence of STEMI-related VA and mortality were obtained prospectively. The corresponding daily levels of the main pollutants were recorded as well as the atmospheric variables. Three cohorts were defined in order to minimize exposure bias. The magnitude of association was estimated using a time-series design and was adjusted according to atmospheric variables. Results The daily rate of hospital admissions for STEMI was associated with increases in PM 2.5, PM 10, lead and NO2 concentrations. VA incidence and mortality were associated with increases in PM 2.5 and PM 10 concentrations. In the most specific cohort, BCN (Barcelona) Attended & Resident, STEMI incidence was associated with increases in PM 2.5 (1.009% per 10μg/m 3 ) and PM 10 concentrations (1.005% per 10μg/m 3 ). VA was associated with increases in PM 2.5 (1.021%) and PM 10 (1.015%) and mortality was associated with increases in PM 2.5 (1.083%) and PM 10 (1.045%). Conclusions Short-term exposure to high levels of PM 2.5 and PM 10 is associated with increased daily STEMI admissions and STEMI-related VA and mortality. Exposure to high levels of lead and NO2 is associated with increased daily STEMI admissions, and NO2 with higher mortality in STEMI patients.

Resumen Introduccion la circulacion pulmonar normal del adulto es un sistema de baja resistencia y alta capacitancia. Conocer su anatomia y fisiologia es importante para comprender los efectos de la enfermedad vascular pulmonar sobre la situacion funcional y pronostico en la hipertension pulmonar. Objetivo analizar las caracteristicas anatomo-funcionales de la circulacion pulmonar y sus cambios con la edad y respuesta al ejercicio. Caracterizar la rigidez arterial pulmonar y su relacion con la poscarga. Metodologia se hizo una revision narrativa de la informacion disponible. Conclusiones la circulacion pulmonar presenta un doble origen: las arterias pulmonares de ‘conduccion’ extraparenquimatosas y las arterias pulmonares de ‘resistencia’ intrapulmonares. La poscarga arterial pulmonar puede estimarse mediante la resistencia vascular (componente estacionario) y la complacencia arterial (componente pulsatil) cuya relacion es inversa y su producto caracteriza la constante de tiempo. La rigidez arterial pulmonar constituye un factor para gobernar la poscarga dinamica, y su aumento constituye un hecho temprano en el desarrollo de hipertension pulmonar. La respuesta de la circulacion pulmonar al ejercicio tiene un rol importante en el diagnostico subclinico de la hipertension pulmonar.

Background: There is a need for improved selection of patients for adjuvant chemotherapy after resection of non-metastatic colorectal cancer (CRC). Regulator of chromosome condensation 2 (RCC2) is a potential prognostic biomarker. We report on the establishment of a robust protocol for RCC2 expression analysis and prognostic tumour biomarker evaluation in patients who did and did not receive adjuvant chemotherapy. Materials and Methods: RCC2 was analysed in 2916 primary CRCs from the QUASAR2 randomised trial and two single-hospital Norwegian series. A new protocol using fluorescent antibody staining and digital image analysis was optimised. Biomarker value for 5-year relapse-free survival was analysed in relation to tumour stage, adjuvant chemotherapy and the molecular markers microsatellite instability, KRAS/BRAFV600E/TP53 mutations and CDX2 expression. Results: Low RCC2 expression was scored in 41% of 2696 evaluable samples. Among patients with stage I–III CRC who had not received adjuvant chemotherapy, low RCC2 expression was an independent marker of inferior 5-year relapse-free survival in multivariable Cox models including clinicopathological factors and molecular markers (HR 1.45, 95% CI 1.09 to 1.94, p=0.012, N=521). RCC2 was not prognostic in patients who had received adjuvant chemotherapy, neither in QUASAR2 nor the pooled Norwegian series. The interaction between RCC2 and adjuvant chemotherapy for prediction of patient outcome was significant in stage III, and strongest among patients with microsatellite stable tumours (pinteraction=0.028). Conclusions: Low expression of RCC2 is a biomarker for poor prognosis in patients with stage I–III CRC and seems to be a predictive biomarker for effect of adjuvant chemotherapy.

Background Improved markers of prognosis are needed to stratify patients with early-stage colorectal cancer to refine selection of adjuvant therapy. The aim of the present study was to develop a biomarker of patient outcome after primary colorectal cancer resection by directly analysing scanned conventional haematoxylin and eosin stained sections using deep learning. Methods More than 12 000 000 image tiles from patients with a distinctly good or poor disease outcome from four cohorts were used to train a total of ten convolutional neural networks, purpose-built for classifying supersized heterogeneous images. A prognostic biomarker integrating the ten networks was determined using patients with a non-distinct outcome. The marker was tested on 920 patients with slides prepared in the UK, and then independently validated according to a predefined protocol in 1122 patients treated with single-agent capecitabine using slides prepared in Norway. All cohorts included only patients with resectable tumours, and a formalin-fixed, paraffin-embedded tumour tissue block available for analysis. The primary outcome was cancer-specific survival. Findings 828 patients from four cohorts had a distinct outcome and were used as a training cohort to obtain clear ground truth. 1645 patients had a non-distinct outcome and were used for tuning. The biomarker provided a hazard ratio for poor versus good prognosis of 3·84 (95% CI 2·72–5·43; p

Background Immunohistochemical quantification of the immune response is prognostic for colorectal cancer (CRC). Here, we evaluate the suitability of alternative immune classifiers on prognosis and assess whether they relate to biological features amenable to targeted therapy. Methods Overall survival by immune (CD3, CD4, CD8, CD20 and FOXP3) and immune-checkpoint (ICOS, IDO-1 and PD-L1) biomarkers in independent CRC cohorts was evaluated. Matched mutational and transcriptomic data were interrogated to identify associated biology. Results Determination of immune-cold tumours by combined low-density cell counts of CD3, CD4 and CD8 immunohistochemistry constituted the best prognosticator across stage II–IV CRC, particularly in patients with stage IV disease (HR 1.98 [95% CI: 1.47–2.67]). These immune-cold CRCs were associated with tumour hypoxia, confirmed using CAIX immunohistochemistry (P = 0.0009), which may mediate disease progression through common biology (KRAS mutations, CRIS-B subtype and SPP1 mRNA overexpression). Conclusions Given the significantly poorer survival of immune-cold CRC patients, these data illustrate that assessment of CD4-expressing cells complements low CD3 and CD8 immunohistochemical quantification in the tumour bulk, potentially facilitating immunophenotyping of patient biopsies to predict prognosis. In addition, we found immune-cold CRCs to associate with a difficult-to-treat, poor prognosis hypoxia signature, indicating that these patients may benefit from hypoxia-targeting clinical trials.

Objective Complex phenotypes captured on histological slides represent the biological processes at play in individual cancers, but the link to underlying molecular classification has not been clarified or systematised. In colorectal cancer (CRC), histological grading is a poor predictor of disease progression, and consensus molecular subtypes (CMSs) cannot be distinguished without gene expression profiling. We hypothesise that image analysis is a cost-effective tool to associate complex features of tissue organisation with molecular and outcome data and to resolve unclassifiable or heterogeneous cases. In this study, we present an image-based approach to predict CRC CMS from standard H&E sections using deep learning. Design Training and evaluation of a neural network were performed using a total of n=1206 tissue sections with comprehensive multi-omic data from three independent datasets (training on FOCUS trial, n=278 patients; test on rectal cancer biopsies, GRAMPIAN cohort, n=144 patients; and The Cancer Genome Atlas (TCGA), n=430 patients). Ground truth CMS calls were ascertained by matching random forest and single sample predictions from CMS classifier. Results Image-based CMS (imCMS) accurately classified slides in unseen datasets from TCGA (n=431 slides, AUC)=0.84) and rectal cancer biopsies (n=265 slides, AUC=0.85). imCMS spatially resolved intratumoural heterogeneity and provided secondary calls correlating with bioinformatic prediction from molecular data. imCMS classified samples previously unclassifiable by RNA expression profiling, reproduced the expected correlations with genomic and epigenetic alterations and showed similar prognostic associations as transcriptomic CMS. Conclusion This study shows that a prediction of RNA expression classifiers can be made from H&E images, opening the door to simple, cheap and reliable biological stratification within routine workflows.

Purpose:The cytokine IL22 promotes tumor progression in murine models of colorectal cancer. However, the clinical significance of IL22 in human colorectal cancer remains unclear. We sought to determine whether the IL22 pathway is associated with prognosis in human colorectal cancer, and to identify mechanisms by which IL22 can influence disease progression.Experimental Design:Transcriptomic data from stage II/III colon cancers in independent discovery (GSE39582 population-based cohort, N = 566) and verification (PETACC3 clinical trial, N = 752) datasets were used to investigate the association between IL22 receptor expression (encoded by the genes IL22RA1 and IL10RB), tumor mutation status, and clinical outcome using Cox proportional hazard models. Functional interactions between IL22 and mutant KRAS were elucidated using human colorectal cancer cell lines and primary tumor organoids.Results:Transcriptomic analysis revealed a poor-prognosis subset of tumors characterized by high expression of IL22RA1, the alpha subunit of the heterodimeric IL22 receptor, and KRAS mutation [relapse-free survival (RFS): HR = 2.93, P = 0.0006; overall survival (OS): HR = 2.45, P = 0.0023]. KRAS mutations showed a similar interaction with IL10RB and conferred the worst prognosis in tumors with high expression of both IL22RA1 and IL10RB (RFS: HR = 3.81, P = 0.0036; OS: HR = 3.90, P = 0.0050). Analysis of human colorectal cancer cell lines and primary tumor organoids, including an isogenic cell line pair that differed only in KRAS mutation status, showed that IL22 and mutant KRAS cooperatively enhance cancer cell proliferation, in part through augmentation of the Myc pathway.Conclusions:Interactions between KRAS and IL22 signaling may underlie a previously unrecognized subset of clinically aggressive colorectal cancer that could benefit from therapeutic modulation of the IL22 pathway.

Neoadjuvant chemoradiotherapy is commonly used to treat rectal cancer but patients have different levels of response and/or toxic effects. As part of the Stratification in COloRecTal cancer (S:CORT) programme, we collected 257 rectal biopsies from two cohorts: Grampian (single hospital) and Aristotle (clinical trial). All patients had been subsequently treated with identical regimen of neoadjuvant radiotherapy and capecitabine. We performed trancriptomic, mutation and copy number profiling and aimed to identify biomarkers associated with the robust pathological endpoint of complete response (CR). Key biological determinants were identified by linear regression of different pre-defined, hypothesis-driven biomarkers for radiotherapy response, adjusted by the known confounders T and N stage. A novel RNA signature was derived using a personalised bioinformatical pipeline using a wide range of machine learning approaches. Results were validated in a publicly available transcriptomic cohort of 107 patients treated with similar dose of radiotherapy and 5-fluorouracil infusion. Further comparision of the biological determinants and the novel RNA signature were performed in the same cohorts and also TCGA by linear regression. Previously published transcriptomic signatures were retrieved and assessed in the validation, unseen cohort. Grampian and Aristotle cohorts had similar statistical power and showed similar associations of CR with biological candidates, 10 of them being significant or borderline (p The immune, stromal and epithelial components of rectal tumours are important players for prediction of CR to radiotherapy in rectal cancer. A 33-gene transcriptomic biomarker can be used to effectively select patients that are highly likely to achieve CR allowing organ preservation while modulation of the relevant biological features in the other patients may be tested to improve their poor outcome with current treatment strategies. Citation Format: Enric Domingo, Sanjay Rathee, Andrew Blake, Leslie M. Samuel, Graeme I. Murray, David Sebag-Montefiore, Simon Gollins, Nicholas West, Rubina Begum, Marian Duggan, Laura White, Susan Richman, Philip Quirke, James Robineau, Keara Redmond, Aikaterini Chatzipli, Ultan McDermott, Ian Tomlinson, Philip Dunne, Francesca Buffa, Tim Maughan. Stratification of radiotherapy and fluoropyrimidine-based chemotherapy from multi-omic profiling in rectal cancer biopsies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr LB129.

The role of the left ventricle in ICU patients with circulatory shock has long been considered. However, acute right ventricle (RV) dysfunction causes and aggravates many common critical diseases (acute respiratory distress syndrome, pulmonary embolism, acute myocardial infarction, and postoperative cardiac surgery). Several supportive therapies, including mechanical ventilation and fluid management, can make RV dysfunction worse, potentially exacerbating shock. We briefly review the epidemiology, pathophysiology, diagnosis, and recommendations to guide management of acute RV dysfunction in ICU patients. Our aim is to clarify the complex effects of mechanical ventilation, fluid therapy, vasoactive drug infusions, and other therapies to resuscitate the critical patient optimally.

Regression of pulmonary hypertension (PH) is often incomplete after successful left-sided valve replacement (LSVR). Proximal pulmonary arterial (PPA) wall disease can be involved in patients with persistent-PH after LSVR, affecting the right ventricular to pulmonary arterial (RV-PA) coupling. Fifteen patients underwent successful LSVR at least one year ago presenting PH by echo (> 50 mmHg). Prosthesis-patient mismatch and left ventricular dysfunction were discarded. All patients underwent hemodynamic and intravascular ultrasound (IVUS) study. We estimated PPA stiffness (elastic modulus [EM]) and the relative area wall thickness (AWT). Acute vasoreactivity was assessed by inhaled nitric oxide (iNO) testing. RV-PA coupling was estimated by the tricuspid annular plane systolic excursion to systolic pulmonary arterial pressure ratio. Patients were classified as isolated post-capillary PH (Ipc-PH; pulmonary vascular resistance [PVR] ≤ 3 WU and/or diastolic pulmonary gradient [DPG] 3 WU and DPG ≥ 7 mmHg). Both Ipc-PH and Cpc-PH showed a significant increase of EM and AWT. Despite normal PVR and DPG, Ipc-PH had a significant decrease in pulmonary arterial capacitance and RV-PA coupling impairment. Cpc-PH had worse PA stiffness and RV-PA coupling to Ipc-PH ( P

BACKGROUND: Precision cancer medicine depends on defining distinct tumour subgroups using biomarkers that may occur at very modest frequencies. One such subgroup comprises patients with exceptionally mutated (ultramutated) cancers caused by mutations that impair DNA polymerase epsilon (POLE) proofreading.METHODS: We examined the association of POLE proofreading domain mutation with clinicopathological variables and immune response in colorectal cancers from clinical trials (VICTOR, QUASAR2, and PETACC-3) and colorectal cancer cohorts (Leiden University Medical Centre 1 and 2, Oslo 1 and 2, Bern, AMC-AJCC-II, and Epicolon-1). We subsequently investigated its association with prognosis in stage II/III colorectal cancer by Cox regression of pooled individual patient data from more than 4500 cases from these studies.FINDINGS: Pathogenic somatic POLE mutations were detected in 66 (1·0%) of 6517 colorectal cancers, and were mutually exclusive with mismatch repair deficiency (MMR-D) in the 6277 cases for whom both markers were determined (none of 66 vs 833 [13·4%] of 6211; pINTERPRETATION: POLE proofreading domain mutations identify a subset of immunogenic colorectal cancers with excellent prognosis. This association underscores the importance of rare biomarkers in precision cancer medicine, but also raises important questions about how to identify and implement them in practice.FUNDING: Cancer Research UK, Academy of Medical Sciences, Health Foundation, EU, ERC, NIHR, Wellcome Trust, Dutch Cancer Society, Dutch Digestive Foundation.

Treatment of pulmonary arterial hypertension has achieved significant progress over the past 20 years. Currently, 3 groups of drugs have proven useful for the treatment of this disease: endothelin receptor antagonist, phosphodiesterase inhibitors and prostacyclin and its analogues. It is recommended to initiate treatment with one of these drugs, the choice depending on the initial severity of patient disease and the preferences of the treating physician. When the patient does not have a satisfactory response, new drugs acting at a different pathway are most commonly added. At this time, considering referral for lung transplantation could be an alternative. Most experts recommend grouping maximum experience in what is known as expert centers. Treatment has led to better survival in these patients, but there is still a long way to cure this life-threatening disease.

Background We report here the prognostic value of ploidy and digital tumour-stromal morphometric analyses using material from 2624 patients with early stage colorectal cancer (CRC). Patients and methods DNA content (ploidy) and stroma-tumour fraction were estimated using automated digital imaging systems and DNA was extracted from sections of formalin-fixed paraffin-embedded (FFPE) tissue for analysis of microsatellite instability. Samples were available from 1092 patients recruited to the QUASAR 2 trial and two large observational series (Gloucester, n = 954; Oslo University Hospital, n = 578). Resultant biomarkers were analysed for prognostic impact using 5-year cancer-specific survival (CSS) as the clinical end point. Results Ploidy and stroma-tumour fraction were significantly prognostic in a multivariate model adjusted for age, adjuvant treatment, and pathological T-stage in stage II patients, and the combination of ploidy and stroma-tumour fraction was found to stratify these patients into three clinically useful groups; 5-year CSS 90% versus 83% versus 73% [hazard ratio (HR) = 1.77 (95% confidence interval (95% CI): 1.13–2.77) and HR = 2.95 (95% CI: 1.73–5.03), P Conclusion A novel biomarker, combining estimates of ploidy and stroma-tumour fraction, sampled from FFPE tissue, identifies stage II CRC patients with low, intermediate or high risk of CRC disease specific death, and can reliably stratify clinically relevant patient sub-populations with differential risks of tumour recurrence and may support choice of adjuvant therapy for these individuals.

It is unclear why among patients with first acute myocardial infarction and an occluded culprit artery only some present ST segment elevation. In fact, there is no study that compares the angiographic area at risk and the collateral circulation in first NSTEMI vs STEMI patients.205 patients admitted for myocardial infarction with occluded culprit artery were included, 132 STEMI and 73 NSTEMI. Demographic data, the area at risk determined by the BARI score and collateral supply by the Rentrop score from the 2 groups were compared. NSTEMI patients showed lower peak Tn I than STEMI in the overall group but also in the 3 subsets with different culprit arteries (p .001). They also presented a higher rate of left circumflex coronary artery (CFX) as culprit artery (52% vs 14%, p .001), smaller BARI score area of the culprit artery (5.4 vs 7.6, p .001), and higher frequency of well-developed collaterals (Rentrop score ≥ 2, 1.82 vs 0.41, p .001). The latter was also higher in each of the 3 different culprit arteries (p = .002-0.001) Among 38 NSTEMI patients with CFX occlusion, 20 with ≥1 mm ST depression in V2 to V4 (possible posterior infarction) showed a similar Rentrop score than the 18 with other ECG changes but lower Tn I peak (p = .012).In first acute myocardial infarction with an occluded culprit artery NSTEMI patients - including those with possible posterior infarction - present smaller infarct size and higher collateral blood supply than STEMI patients in each of the 3 main culprit arteries.

Intratumoural T-cell infiltrate intensity cortes wrelaith clinical outcome in stage II/III colorectal cancer (CRC). We aimed to determine whether this association varies across this heterogeneous group.We performed a pooled analysis of 1804 CRCs from the QUASAR2 and VICTOR trials. Intratumoural CD8In QUASAR2, intratumoural CD8The prognostic value of intratumoural CD8

Background: The tumor microenvironment is a key feature to understand cancer biology and may be used clinically. Quantification of tissue composition is usually based either on visual pathological review (VPR) or deconvolution of whole genome molecular data. Although the former is a direct measurement it has modest reproducibility while the latter is an indirect measurement of unclear accuracy, expensive and not always available. Here we test digital pathology coupled with machine learning as a new tool to assess tissue composition. Methods: As part of the Stratification in COloRecTal cancer (S:CORT) programme, a set of over 500 colorectal cancer (CRC) archival paraffin blocks from resections and biopsies were sequentially sectioned for Hematoxylin and Eosin staining (H&E), RNA extraction, a second H&E and DNA extraction. RNA expression microarrays, targeted DNA sequencing and DNA methylation arrays were applied. Tissue composition from the H&Es was obtained by VPR of expert pathologists and by a deep neural net (DNN) algorithm after supervised training on >1,500 tissue areas from S:CORT, TCGA, TEM and CORGI CRC cohorts. Tumor purity estimates were obtained from RNA and methylation arrays. Results: DNN estimates including area and cell counts were obtained for tumor, desmoplastic stroma, inflamed stroma, mucin/hypocellular stroma, muscle, necrosis and white space. An average of 6.8x105 total cells (range: 1.2x104-2.8x106) and 1.2x105 (range: 7.2x104-1.8x106) were classified for resections and biopsies respectively. Analyses performed twice on the same H&Es obtained matching results (r=1.0). Comparison of the paired first and second H&E showed very high correlations (r~0.9) and total cell counts correlated with DNA and RNA extraction yields (r~0.6). Tumor purity estimates by VPR mildly correlated with DNN (r~0.5) but they were underestimated and very variable. As a result, copy number adjusted by VPR purity tended to be overestimated compared to adjustment with DNN estimates. The improved performance of DNN is reflected in an accurate capture of non-linear association between area and cell counts in invasive cancer. In contrast, tumor purity estimates derived from RNA or DNA methylation arrays showed better correlations compared with DNN (r~0.6) but both overestimated purity in cases with low cell counts by up to a three-fold difference. Conclusions: Tissue composition analysis with DNN allows analytical robustness, automatization and standardization and provides very high reproducibility at single cell resolution. DNN-based estimation of tumor purity is more accurate than VPR or extrapolation from molecular data derived from genome-wide omic platforms which tend to under and overestimate tumor purity respectively. DNN could be used to better plan and asses downstream molecular analyses and to investigate tissue-based metrics as potential clinical biomarkers in clinical trials. Citation Format: Enric Domingo, Aikaterini Chatzipli, Susan Richman, Andrew Blake, Claire Hardy, Celina Whalley, Keara Redmon, Ian Tomlinson, Philip Dunne, Steven Walker, Andrew Beggs, Ultan McDermott, Graeme I. Murray, Leslie M. Samuel, Matthew Seymour, Philip Quirke, Tim Maughan, Viktor H. Koelzer. Assessment of tissue composition with digital pathology in colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4446.

Upstream impedance could characterise the RV afterload and the relative contribution of large and small vessel disease in PH, regardless of the PAOP, including the inverse relationship with HR as an indirect RV functional responsehttp://ow.ly/fqvN30nbNFo

We read with great interest the recent article by Sharma et al. [1] on the evaluation of right ventricular (RV) reserve in pulmonary arterial hypertension (PAH) by the dobutamine stress test. Their work highlights the potential clinical value of the RV systolic reserve into the evaluation of PAH patients beyond resting measurements. Sharma et al. [1] reported that RV contractile reserve (tricuspid annular plane systolic excursion (TAPSE) and tricuspid annulus systolic myocardial velocity ( S ′)) is markedly attenuated in PAH patients and correlates with exercise capacity. Although the merit of the work is in assessing RV contractile reserve by direct functional parameters, there are some topics that deserve discussion. Patients with PAH exhibit markedly diminished RV contractile reserve and pulmonary arterial vascular reserve

Objectives The spectrum of patients with 'angina and normal coronary arteries' ranges from severe vasospasm to atypical chest pain. Among those with typical angina, however, little is known about similarities in the clinical profile and circadian presentation between typical nonvasospastic angina and normal coronary arteries (tANCA) and vasospastic angina (VA). Materials and methods Clinical, ECG, and angiographic features as well as the circadian characteristics of angina were compared between 384 tANCA and 273 VA patients. Follow-up events were also analyzed. Results tANCA patients had greater female predominance (61 vs. 18%), higher incidence of dyspnea to moderate exertion (49 vs. 12%), lower incidence of tobacco smoking (25 vs. 67%), but a similar low rate of diabetes (8.9 vs. 4.4%). In both groups, however, dyspnea and smoking were associated with female and male sex, respectively. tANCA patients showed lower but non-negligible frequency of early morning (25 vs. 67%) and evening angina (37 vs. 54%), similar rate of nocturnal angina (47 vs. 50%), and higher rate of emotional angina (49 vs. 31%). Moreover, a high proportion of patients gained pain relief with nitroglycerin (97% in VA, 246/253, and 76% in tANCA, 231/306). At 140 months, frequent angina (>10 episodes/year) was rare (VA: 7.1% vs. tANCA: 6.3%) as was the rate of cardiac death/myocardial infarction (7.3 vs. 6.0%, P=0.524). Conclusion Despite differences in the clinical profile between VA and tANCA patients, there is notable sharing of circadian presentation of rest angina, response to nitroglycerin, and long-term presence and frequency of angina that suggests more similarities in underlying mechanisms than heretofore suspected.

Background Antiangiogenic agents have established efficacy in the treatment of metastatic colorectal cancer. We investigated whether bevacizumab could improve disease-free survival in the adjuvant setting after resection of the primary tumour. Methods For the open-label, randomised, controlled QUASAR 2 trial, which was done at 170 hospitals in seven countries, we recruited patients aged 18 years or older with WHO performance status scores of 0 or 1 who had undergone potentially curative surgery for histologically proven stage III or high-risk stage II colorectal cancer. Patients were randomly assigned (1:1) to receive eight 3-week cycles of oral capecitabine alone (1250 mg/m2 twice daily for 14 days followed by a break for 7 days) or the same regimen of oral capecitabine plus 16 cycles of 7·5 mg/kg bevacizumab by intravenous infusion over 90 min on day 1 of each cycle. Randomisation was done by a computer-generated schedule with use of minimisation with a random element stratified by age, disease stage, tumour site, and country. The study was open label and no-one was masked to treatment assignment. The primary endpoint was 3-year disease-free survival, assessed in the intention-to-treat population. Toxic effects were assessed in patients who received at least one dose of randomised treatment. This trial is registered with the ISRCTN registry, number ISRCTN45133151. Findings Between April 25, 2005, and Oct 12, 2010, 1952 eligible patients were enrolled, of whom 1941 had assessable data (968 in the capecitabine alone group and 973 in the capecitabine and bevacizumab group). Median follow-up was 4·92 years (IQR 4·00–5·16). Disease-free survival at 3 years did not differ between the groups (75·4%, 95% CI 72·5–78·0 in the capecitabine and bevacizumab group vs 78·4%, 75·7–80·9 in the capecitabine alone group; hazard ratio 1·06, 95% CI 0·89–1·25, p=0·54). The most common grade 3–4 adverse events were hand–foot syndrome (201 [21%] of 963 in the capecitabine alone group vs 257 [27%] of 959 in the capecitabine and bevacizumab group) and diarrhoea (102 [11%] vs 104 [11%]), and, with the addition of bevacizumab, expected increases were recorded in all-grade hypertension (320 [33%] vs 75 [8%]), proteinuria (197 [21%] vs 49 [5%]), and wound healing problems (30 [3%] vs 17 [2%]). 571 serious adverse events were reported (221 with capecitabine alone and 350 with capecitabine and bevacizumab). Most of these were gastrointestinal (n=245) or cardiovascular (n=169). 23 deaths within 6 months of randomisation were classified as being related to treatment, eight in the capecitabine alone group and 15 in the capecitabine and bevacizumab group. Interpretation The addition of bevacizumab to capecitabine in the adjuvant setting for colorectal cancer yielded no benefit in the treatment of an unselected population and should not be used.

Background: Pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH) are serious diseases with similar pathophysiologic aspects. The prognosis of patients with these conditions is highly uncertain, particularly incident cases. Methods: A Cox proportional hazards model was applied to a group of 85 patients (81% women, mean age 52 (18 - 82) years) with PAH (80%) and non-surgical CTEPH (20%) to evaluate risk factors for mortality. The following variables were included in the model: age, etiology, baseline 6-minute walk test (6 mWT), cardiac index, and improvement in the 6 mWT following initiation of first medical treatment. Results: In the multivariate analysis, the response to treatment, assessed by an improvement on the 6 mWT, was the most relevant prognostic factor in these patients (RR, 4.832 (95% CI, 1.888 - 12.364); p = 0.001). The remaining variables studied in this model had less influence on the prognosis: age > 50 years (RR, 0.744 (95% CI, 0.26 - 2.133); p = 0.582); etiology of connective tissue disease-associated PAH (RR, 3.145 (95% CI, 0.995-9.946); p = 0.051) or CTEPH (RR, 0.654 (95% CI, 0.179 - 2.387); p = 0.521) with respect to idiopathic PAH; baseline 6 mWT (RR, 1.173 (95% CI, 0.599 - 4.895); p = 0.315); or cardiac index (RR, 2.295 (95% CI, 0.793 - 6.642); p = 0.125). Conclusions: There is a high degree of uncer-tainty regarding the prognosis of PAH and CTEPH at the start of appropriate treatment. Our results support the idea that the initial treatment response is of paramount importance as prognostic factor in these patients.

Background The cause of coronary vasoconstriction in patients with angina at rest, nonsignificant coronary stenosis, and endothelial dysfunction remains unknown. Our objective was to investigate the association between enhanced coronary vasoconstriction and increased circulating levels of vasoconstrictor agents. Methods Plasma levels of big endothelin-1, serotonin, and superoxide produced by polymorphonuclear leukocytes were measured in 38 patients with stable angina at rest without significant coronary artery stenosis—23 with nonvasospastic angina and 15 with vasospastic angina—and were compared with 10 patients with stable coronary disease and 20 age-matched controls. Results Patients with angina at rest showed higher big endothelin-1 (1.28 vs 0.72 fmol/mL, P 0.001), serotonin (18.0 vs 9.1 ng/mL, P = 0.002), and superoxide produced by polymorphonuclear leukocytes (177 vs 67 nmol/10 × E8 × minutes, P = 0.001) than did controls. Serotonin and superoxide produced by polymorphonuclear leukocytes were also higher than in coronary disease patients (5.4 ng/mL, P = 0.001, and 97 nmol/10 x E8 x minutes, P = 0.005), and big endothelin-1 levels tended to be higher (0.99 fmol/mL, P = 0.073). Moreover, there were no significant differences in these 3 parameters between patients with vasospastic and nonvasospastic angina, and among the latter, between patients with a positive and those with a negative exercise stress test. Conclusion Systemic plasma levels of agents with the potential to produce coronary vasoconstriction are increased in patients with stable vasospastic or nonvasospastic angina and, hence, may contribute to their angina, increased coronary tone, and impaired vasodilatory capacity. Furthermore, they may establish a mechanistic link between the 2 conditions.

AIMS To evaluate the feasibility and safety of the Nile Croco® coronary bifurcation stent system (Minvasys, Gennevilliers, France). METHODS AND RESULTS The primary endpoint was to assess the acute device success and angiographic success with the use of the Nile Croco® stent system. Secondary endpoints included in-hospital and six month major cardiac events (MACE).There were 151 consecutive patients enrolled in the Nile Croco Study at Vall Hebron Hospital. The Nile Croco® stent was successfully implanted in 144 patients (95.4%) and final angiographic success was obtained in 100% of the patients. 138 out of the 151 (91%) patients included have accomplished the six month follow-up. There was one in-hospital MACE in the 151 recruited patients. The MACE rate at six months in the 138 patients with follow-up was 14% and the ischaemia-driven TLR rate was 7.2 %. CONCLUSIONS The results of our Nile Croco® Study are the first to demonstrate the safety and high performance of this dedicated stent system for the treatment of bifurcation lesions. The device can be successfully implanted in more than 95% of all cases, with a high procedural success rate and low in-hospital and six month MACE rates.

3515Background: The intensity of the T cell anti-tumour response influences colorectal cancer (CRC) outcome, and may predict benefit from immunomodulatory therapies. However, previous studies have ...

A 64-year-old diabetic and dyslipidemic woman was admitted to our hospital with a history of 3 episodes of acute pulmonary edema in the past 4 months, without evidence of organic heart disease. She was affected by a hypopituitarism and was treated with levothyroxine and desmopressin. She had atypical chest pain 1 year before, but 2 exercise stress tests were negative. In the past 4 months, she had been admitted 3 times for severe dyspnea at rest of sudden onset without chest pain, requiring endotracheal intubation because of severe acute pulmonary edema. Basal physical examination was normal. ECGs and serial troponin levels were normal. Clinical treatment was successful with early extubation. Echocardiography (echo) at rest was completely normal with normal left ventricular systolic and diastolic function and no valvular regurgitations. Coronary angiography revealed normal coronary arteries and normal global and regional left ventricular systolic motion. Thoracoabdominal computerized tomography was normal; and pulmonary thromboembolism, aortic disease, and suprarenal tumor were ruled out. Pulmonary biopsy also was normal. Laboratory tests including hemoglobin, electrolytes, autoantibodies, catecholamine, and thyroid hormones were also normal. Holter and telemetry did not reveal arrhythmias. Gated single-photon emission computed tomography and stress echo were negative for ischemia. Most of …

Pulmonary arterial hypertension (PAH) is a rare fatal disease defined as a sustained elevation of pulmonary arterial pressure to more than 25 mmHg at rest, with a mean pulmonary-capillary wedge pressure and left ventricular enddiastolic pressure of less than 15 mmHg at rest. Histopathology of PAH is founded on structural modifications on the vascular wall of small pulmonary arteries characterized by thickening of all its layers. These changes, named as vascular remodelling, include vascular proliferation, fibrosis, and vessel obstruction. In clinical practice the diagnosis of PAH relies on measurements of pulmonary vascular pressure and cardiac output, and calculation of pulmonary vascular resistances. Direct evaluation of pulmonary vascular structure is not routinely performed in pulmonary hypertension since current imaging techniques are limited and since little is known about the relationship between structural changes and functional characteristics of the pulmonary vasculature. Intravascular ultrasound studies in patients with pulmonary hypertension have shown a thicker middle layer, increased wall-thickness ratio and diminished pulsatility than in control patients. Optical Coherence Tomography, a new high resolution imaging modality that has proven its superiority over intravascular ultrasound (IVUS) for the detection and characterization of coronary atherosclerotic plaque composition, may potentially be a useful technique for the in vivo study of the pulmonary arterial wall. In addition current progress in Echo Doppler technique will quantify right ventricular function with parameters independent of loading conditions and not requiring volumetric approximations of the complex geometry of the right ventricle. This would allow the in vivo study of right ventricular and pulmonary artery remodelling in PAH.

La enfermedad cardiovascular es la principal causa de morbilidad y mortalidad en los pacientes con diabetes mellitus. Se ha demostrado que los pacientes diabeticos presentan una mayor incidencia de enfermedad coronaria multivaso, con mayor frecuencia de lesiones complejas, pobres lechos distales y una progresion de la enfermedad mas rapida que la poblacion general no diabetica. La revascularizacion coronaria percutanea (ICP) ha demostrado su utilidad en los pacientes diabeticos. Sin embargo, aunque los resultados angiograficos iniciales son buenos, hay una mayor incidencia de reestenosis, un riesgo mas elevado de complicaciones y una menor supervivencia a largo plazo. Los stents farmacoactivos han reducido notablemente el riesgo de reestenosis y complicaciones tardias. En espera de los resultados de los estudios actualmente en marcha, en los pacientes diabeticos con enfermedad multivaso, la cirugia de derivacion aortocoronaria sigue siendo el tratamiento de primera eleccion. Sin embargo, hay que destacar que, desde un punto de vista practico, a la hora de indicar cirugia de derivacion aortocoronaria o ICP deberemos basarnos en las caracteristicas particulares del paciente (p. ej., comorbilidad asociada) y en la experiencia del propio centro, ya que hay notables diferencias en funcion de la experiencia del equipo quirurgico y de cardiologia intervencionista. Por ultimo, es muy importante destacar que, en los pacientes diabeticos en los que se realiza revascularizacion coronaria, con independencia del metodo utilizado, es de trascendental importancia establecer un tratamiento medico energico que incluya modificaciones en el estilo de vida (tabaquismo, sindrome metabolico, etc.), ntiagregacion plaquetaria, tratamiento con estatinas en las dosis adecuadas (objetivo terapeutico con un valor de colesterol unido a lipoproteinas de baja densidad

Objetivo El tratamiento con bosentan mejora la capacidad de ejercicio de los pacientes con hipertension pulmonar. Son muy escasos los estudios que evaluan este tratamiento a largo plazo, que es el objetivo propuesto en el presente trabajo. Pacientes y metodos Un grupo de 22 pacientes –18 mujeres y 4 varones, con una edad media de 45,5 anos (rango: 19-77 anos)– con hipertension pulmonar en clase functional III recibieron tratamiento con bosentan entre abril de 2002 y junio de 2005. La hipertension pulmonar era idiopatica en 10 casos y estaba asociada a cardiopatia corregida (n = 4), esclerodermia (n = 4), embolia periferica (n = 3) e hipertension portal (n = 1) en los restantes. Se estudiaron los datos clinicos y hemodinamicos y los cambios que habian experimentado desde el inicio del tratamiento hasta el fin del estudio. Resultados El seguimiento medio de los pacientes fue de 15,7 meses (rango: 12,6-31,8). La clase funcional mejoro o se estabilizo a los 3 meses de tratamiento en 21 (95%) y al ano en 14 (64%). La distancia recorrida en la prueba de la marcha de 6 min se incremento a los 3 meses de tratamiento una media de 64,5 m, mejoria que se mantuvo a los 6, 12 y 18 meses. El tratamiento se interrumpio en 4 pacientes (18%): por muerte en 2 casos, por empeoramiento en uno y por in-tolerancia a la medicacion en otro. En otros 4 pacientes (18%) se objetivo falta de eficacia. Ningun paciente presento hepatotoxicidad remarcable. Conclusiones Los resultados del presente estudio apoyan la idea de que el tratamiento con bosentan se asocia a una mejoria clinica y de la capacidad de ejercicio a largo plazo en aproximadamente dos terceras partes de los pacientes con hipertension pulmonar.

We investigated to what extent patients with variant angina and significant coronary stenosis (or=70%) present a clinical and angiographic profile similar to patients with ST elevation myocardial infarction. Thus, the clinical and angiographic features as well as follow-up events of 200 patients were prospectively analyzed and were compared with those of 422 patients with a first ST elevation myocardial infarction survivors of the early phase (3 days) and those of 70 patients with variant angina and non significant stenosis. Age and incidence of smoking, systemic hypertension, diabetes and maximum ST elevation were similar in the 2 groups. Furthermore, among patients with significant coronary stenosis, stenosis severity and the proportion of eccentric lesions were also comparable. Incidence of recent-within 30 days prior to admission-angina at rest was higher in variant angina patients with significant stenosis (67% vs. 27%, p0.001) than in those with myocardial infarction but long standing angina at rest (30 days) was low and comparable in these 2 groups (15% vs. 11%, ns). Also, in a 5-year follow-up most patients from these 2 groups were free from angina at rest (86% vs. 84%) which in variant angina patients was largely attributable to a high revascularization rate (72%). Moreover, the rate of myocardial infarction/cardiac death (20% vs. 19%) was also similar. Patients with variant angina and non-significant stenosis, however, had longer antecedent angina, more frequent follow-up angina and a lower incidence of cardiac events than the other 2 groups. Thus, these findings suggest that patients with variant angina and significant coronary stenosis generally behave as an acute coronary syndrome-likely associated with an acutely complicated plaque-rather than as recurrent vasospastic angina, and should be managed accordingly.

Several studies have demonstrated a correlation between myocardial ischemia and severity of coronary lesions as determined by intravascular ultrasound (IVUS) and fractional flow reserve (FFR) measurements. However, their value for the assessment of mild coronary stenoses that are associated with myocardial perfusion abnormalities has not been well studied. The objective of this study was to prospectively compare the results of myocardial perfusion as determined by exercise/dipyridamole myocardial single-photon emission computed tomography with IVUS and FFR measurements in patients who had angiographically mild coronary stenosis (50% diameter stenosis by quantitative coronary angiography). Forty-eight patients who had stable coronary disease (61 +/- 11 years of age; 6 women) were included. All had mild coronary stenosis in the proximal/middle segment ofor = 1 coronary artery and had undergone maximal exercise myocardial technetium-99m tetrofosmin single-photon emission computed tomography within 48 hours before coronary angiography. IVUS measurements included lesion lumen area, external elastic membrane area, lesion plaque burden (calculated as external elastic membrane minus lumen area, divided by external elastic membrane, and multiplied by 100), and lumen area stenosis (calculated as reference lumen area minus lesion lumen area, divided by reference lumen area, multiplied by 100). Fifty-three coronary lesions were studied, with a mean percent diameter stenosis of 34.9 +/- 7.9% on angiography. Myocardial perfusion defects were demonstrated by single-photon emission computed tomography in 11 patients (12 myocardial regions) with no differences in lesion percent diameter stenosis compared with those without perfusion defects. The presence of reversible perfusion defects was associated with a higher lesion plaque burden as evaluated by IVUS (67.4 +/- 8.1% vs 60.2 +/- 9.3%, p = 0.01). FFR values did not differ in the presence or absence of perfusion defects (0.90 +/- 0.06 vs 0.92 +/- 0.07, respectively; p = NS). In conclusion, plaque burden as determined by IVUS may partly explain the presence of myocardial perfusion defects in cases of angiographically nonsignificant coronary lesions. However, the high FFR values associated with these lesions suggest that other mechanisms, such as endothelial/microvascular dysfunction, might also account for perfusion abnormalities in these patients.

Deep negative T waves (NTW) are a frequent finding following acute ST-segment elevation coronary syndromes but its possible relation with the status of regional contractility remains unclear. We studied 52 patients with a first ST-elevation acute coronary syndrome with or without NTW in anterior leads (≥3 mm in ≥3 leads) and assessed the ejection fraction and regional myocardial contractility by contrast left ventriculography at baseline and during a low-dose dobutamine test (10 μ g/kg per minute). Ejection fraction and regional contractility tended to be more preserved in patients with NTW, but dobutamine increased regional contractility in the jeopardized area in most patients with or without NTW and the improvement was similar in those either with or without enzyme elevation. In conclusion, deep NTW after ST-elevation acute coronary syndromes tends to be associated with a more preserved myocardium but it is neither a sensitive nor a specific marker of viable myocardium.

Objective: To assess the structural and functional characteristics of pulmonary arteries by intravascular ultrasound (IVUS) in the setting of primary pulmonary hypertension, and to correlate the ultrasound findings with haemodynamic variables and mortality at follow up. Design: Prospective observational study. Setting: University hospital (tertiary referral centre). Patients: 20 consecutive patients with primary pulmonary hypertension (16 female; mean (SD) age, 39 (14) years). Methods: Cardiac catheterisation and simultaneous IVUS of pulmonary artery branches at baseline and after infusion of epoprostenol. Results: 33 pulmonary arteries with a mean diameter of 3.91 (0.80) mm were imaged, and wall thickening was observed in all cases, 64% being eccentric. Mean wall thickness was 0.37 (0.13) mm, percentage wall area 31.0 (9.3)%, pulsatility 14.6 (4.8)%, and pulmonary/elastic strain index 449 (174) mm Hg. No correlation was observed between IVUS findings and haemodynamic variables. Epoprostenol infusion increased pulsatility by 53% and decreased the pulmonary/elastic strain index by 41% (p = 0.0001), irrespective of haemodynamic changes. At 18 (12) months follow up, nine patients had died. A reduced pulsatility and an increased pulmonary/elastic strain index were associated with increased mortality at follow up (12.0 (4.4)% v 16.4 (4.4)%, p = 0.03; 369 (67) v 546 (216) mm Hg, p = 0.02). Conclusions: IVUS demonstrated pulmonary artery wall abnormalities in all patients with primary pulmonary hypertension, mostly eccentric. The severity of the changes did not correlate with haemodynamic variables, and epoprostenol improved pulmonary vessel stiffness. There was an association between impaired pulmonary artery functional state as determined by IVUS and mortality at follow up.

The effect of the C677T polymorphism in the methylenetetrahydrofolate reductase (MTHFR) gene, traditionally associated with ischaemic heart disease (IHD), was assessed in a Spanish population. The transmission disequilibrium test (TDT) was used to determine a possible association in a sample of 101 trios of IHD patients. The distribution of MTHFR genotypes was similar in the IHD subjects and the parental group; the TT genotype was present in 14.9% of IHD patients, as compared to 15.2% in the parents. The frequency of the T allele was also similar in IHD cases and parents (39.6% vs. 42.4%; p = 0.649). The TDT confirmed that the observed transmission of the T allele did not deviate significantly from the expected one (chi2 = 0.743; p > 0.4). Our TDT analysis clearly demonstrates a lack of association between the T allele of the C677T mutation in MTHFR and cardiovascular artery disease, both for the general group and for different risk subgroups (smokers, hypertension, male sex, overweight and type A behaviour pattern) in the Spanish population.

Through the nitric oxide (NO) production in the vascular system, the endothelial nitric oxide synthase (eNOS or NOS3) is a key enzyme in blood pressure regulation and atherosclerosis control. Several previous studies have suggested an important role of eNOS as a genetic risk factor for cardiovascular diseases. In this context, a genetic association study was carried out between two eNOS polymorphisms (the ecNOS4a/b VNTR and the G894T substitution) in a sample of 101 nuclear families having one affected offspring of ischemic heart disease (IHD). Transmission disequilibrium test (TDT) revealed partial associations between the VNTR marker and IHD in patients with a type A behavior pattern (TABP) (P = 0.0325, RR = 3.67) and for the haplotype formed by variant b of the VNTR and the T mutation of the G894T substitution in the IHD-affected subgroup having body mass index (BMI) lower than 25 (P = 0.0348, RR = 0.22). However, once multiple testing correction was applied, the associations became nonsignificant. A significant effect of the haplotype b-G increasing high-density lipoprotein cholesterol (HDL-C) plasma levels was detected (P = 0.021 after Bonferroni correction). From a population point of view, frequencies found for G894T substitution in Spain were significantly different from other populations.

If we were to summarize the rationale that underpins medical oncology in a Latin aphorism, it might be 'veneno ergo sum'; that is, I poison, therefore I am. The burden of chemotherapy-associated toxicity is well recognized, but we have relatively few tools that increase the precision of anticancer drug prescribing. We propose a shift in emphasis from the focussed study of polymorphisms in drug metabolic pathways in small sets of patients to broader agnostic analyses to systematically correlate germline genetic variants with adverse events in large, well-defined cancer populations. Thus, we propose the new science of 'toxgnostics' (that is, the systematic, agnostic study of genetic predictors of toxicity from anticancer therapy). © 2014 Macmillan Publishers Limited.

The clinical, angiographic and therapeutic features of eight patients who developed a left ventricular pseudoaneurysm (PA) after an acute myocardial infarction (AMI) and those of 25 who did not develop this complication following a medically managed left ventricular free wall rupture (FWR) were compared. These 25 patients were treated with pericardiocentesis, extended rest and strict blood pressure control. Most patients with FWR or PA had a first AMI and absence of overt heart failure. Both groups had a comparable age, frequency of systemic hypertension and extent of coronary disease. Pericardial effusion (> or =10 mm) was documented in all patients with FWR and in two of the three with PA with this information. Twenty four patients with FWR were hospitalized within the first 48 h (96%) but only three of those with PA (37.5%, P

Introduccion y objetivos La ergometria convencional presenta limitaciones en la valoracion de la permeabilidad de los injertos aortocoronarios. El motivo del presente estudio fue determinar la eficacia de la tomogammagrafia miocardica de esfuerzo con compuestos tecneciados para el diagnostico de la enfermedad de los injertos aortocoronarios poscirugia cardiaca. Pacientes y metodos Se analizo de forma retrospectiva el estado de 67 injertos coronarios (31 de arteria mamaria, 36 de vena safena, 35 a la arteria descendente anterior, 15 a la circunfleja y 17 a la coronaria derecha) pertenecientes a 38 pacientes (63 ± 8,7 anos; 35 varones). El tiempo medio entre la intervencion quirurgica y la tomogammagrafia de esfuerzo fue de 9,7 anos. De las 38 tomogammagrafias, 16 fueron realizadas con 99mTc-MIBI y las restantes 22 con 99mTc-tetrofosmina. En 6 de los casos se administro dipiridamol intravenoso durante la realizacion de una prueba de esfuerzo insuficiente. Resultados La sensibilidad (73,1%), especificidad (93%), valor predictivo positivo (86,3%), valor predictivo negativo (84,4%), valor global (85%), coeficiente de probabilidad positivo (10,4) y coeficiente de probabilidad negativo (0,29) de la tomogammagrafia fueron significativamente mejores (p Conclusiones La tomogammagrafia miocardica de esfuerzo con componentes tecneciados es una exploracion de alta eficacia para el diagnostico de la enfermedad de los injertos coronarios.