Multivariate machine learning models for prediction of pathologic response to neoadjuvant therapy in breast cancer using MRI features: a study using an independent validation set.

PURPOSE: To determine whether a multivariate machine learning-based model using computer-extracted features of pre-treatment dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) can predict pathologic complete response (pCR) to neoadjuvant therapy (NAT) in breast cancer patients. METHODS: Institutional review board approval was obtained for this retrospective study of 288 breast cancer patients at our institution who received NAT and had a pre-treatment breast MRI. A comprehensive set of 529 radiomic features was extracted from each patient's pre-treatment MRI. The patients were divided into equal groups to form a training set and an independent test set. Two multivariate machine learning models (logistic regression and a support vector machine) based on imaging features were trained to predict pCR in (a) all patients with NAT, (b) patients with neoadjuvant chemotherapy (NACT), and (c) triple-negative or human epidermal growth factor receptor 2-positive (TN/HER2+) patients who had NAT. The multivariate models were tested using the independent test set, and the area under the receiver operating characteristics (ROC) curve (AUC) was calculated. RESULTS: Out of the 288 patients, 64 achieved pCR. The AUC values for predicting pCR in TN/HER+ patients who received NAT were significant (0.707, 95% CI 0.582-0.833, p < 0.002). CONCLUSIONS: The multivariate models based on pre-treatment MRI features were able to predict pCR in TN/HER2+ patients.

Association of distant recurrence-free survival with algorithmically extracted MRI characteristics in breast cancer.

BACKGROUND: While important in diagnosis of breast cancer, the scientific assessment of the role of imaging in prognosis of outcomes and treatment planning is limited. PURPOSE: To evaluate the potential of using quantitative imaging variables for stratifying risk of distant recurrence in breast cancer patients. STUDY TYPE: Retrospective. POPULATION: In all, 892 female invasive breast cancer patients. SEQUENCE: Dynamic contrast-enhanced MRI with field strength 1.5 T and 3 T. ASSESSMENT: Computer vision algorithms were applied to extract a comprehensive set of 529 imaging features quantifying size, shape, enhancement patterns, and heterogeneity of the tumors and the surrounding tissue. Using a development set with 446 cases, we selected 20 imaging features with high prognostic value. STATISTICAL TESTS: We evaluated the imaging features using an independent test set with 446 cases. The principal statistical measure was a concordance index between individual imaging features and patient distant recurrence-free survival (DRFS). RESULTS: The strongest association with DRFS that persisted after controlling for known prognostic clinical and pathology variables was found for signal enhancement ratio (SER) partial tumor volume (concordance index [C] = 0.768, 95% confidence interval [CI]: 0.679-0.856), tumor major axis length (C = 0.742, 95% CI: 0.650-0.834), kurtosis of the SER map within tumor (C = 0.640, 95% CI: 0.521-0.760), tumor cluster shade (C = 0.313, 95% CI: 0.216-0.410), and washin rate information measure of correlation (C = 0.702, 95% CI: 0.601-0.803). DATA CONCLUSION: Quantitative assessment of breast cancer features seen in a routine breast MRI might be able to be used for assessment of risk of distant recurrence. LEVEL OF EVIDENCE: 4 Technical Efficacy: Stage 6 J. Magn. Reson. Imaging 2019.

Intra-tumor molecular heterogeneity in breast cancer: definitions of measures and association with distant recurrence-free survival.

PURPOSE: The purpose of the study was to define quantitative measures of intra-tumor heterogeneity in breast cancer based on histopathology data gathered from multiple samples on individual patients and determine their association with distant recurrence-free survival (DRFS). METHODS: We collected data from 971 invasive breast cancers, from 1st January 2000 to 23rd March 2014, that underwent repeat tumor sampling at our institution. We defined and calculated 31 measures of intra-tumor heterogeneity including ER, PR, and HER2 immunohistochemistry (IHC), proliferation, EGFR IHC, grade, and histology. For each heterogeneity measure, Cox proportional hazards models were used to determine whether patients with heterogeneous disease had different distant recurrence-free survival (DRFS) than those with homogeneous disease. RESULTS: The presence of heterogeneity in ER percentage staining was prognostic of reduced DRFS with a hazard ratio of 4.26 (95% CI 2.22-8.18, p < 0.00002). It remained significant after controlling for the ER status itself (p < 0.00062) and for patients that had chemotherapy (p < 0.00032). Most of the heterogeneity measures did not show any association with DRFS despite the considerable sample size. CONCLUSIONS: Intra-tumor heterogeneity of ER receptor status may be a predictor of patient DRFS. Histopathologic data from multiple tissue samples may offer a view of tumor heterogeneity and assess recurrence risk.

Dissecting the regulation of bile-induced biofilm formation in Staphylococcus aureus.

Aspiration of bile into the cystic fibrosis (CF) lung has emerged as a prognostic factor for reduced microbial lung biodiversity and the establishment of often fatal, chronic pathogen infections. Staphylococcus aureus is one of the earliest pathogens detected in the lungs of children with CF, and once established as a chronic infection, strategies for its eradication become limited. Several lung pathogens are stimulated to produce biofilms in vitro in the presence of bile. In this study, we further investigated the effects of bile on S. aureus biofilm formation. Most clinical S. aureus strains and the laboratory strain RN4220 were stimulated to form biofilms with sub-inhibitory concentrations of bovine bile. Additionally, we observed bile-induced sensitivity to aminoglycosides, which we exploited in a bursa aurealis transposon screen to isolate mutants reduced in aminoglycoside sensitivity and augmented in bile-induced biofilm formation. We identified five mutants that exhibited hypersensitivity to bile with respect to bile-induced biofilm formation, three of which carried transposon insertions within gene clusters involved in wall teichoic acid (WTA) biosynthesis or transport. Strain TM4 carried an insertion between the divergently oriented tagH and tagG genes, which encode the putative WTA membrane translocation apparatus. Ectopic expression of tagG in TM4 restored a wild-type bile-induced biofilm response, suggesting that reduced translocation of WTA in TM4 induced sensitivity to bile and enhanced the bile-induced biofilm formation response. We propose that WTA may be important for protecting S. aureus against exposure to bile and that bile-induced biofilm formation may be an evolved response to protect cells from bile-induced cell lysis.

Managing lower urinary tract symptoms in primary care: qualitative study of GPs' and patients' experiences.

BACKGROUND: Lower urinary tract symptoms (LUTS) are common in males aged ≥40 years and have a considerable impact on quality of life. Management can be complex, and although most LUTS could be treated effectively in primary care, referrals to urology outpatients are increasing. AIM: To explore GPs' experiences of managing LUTS together with patients' experiences of and preferences for treatment in primary care. DESIGN AND SETTING: Telephone interviews were conducted with GPs and male patients presenting to primary care with bothersome LUTS. METHOD: Eleven GPs and 25 male patients were purposively sampled from 20 GP practices in three UK regions: Newcastle upon Tyne, Bristol, and South Wales. Interviews were conducted between May 2018 and January 2019, and were analysed using a framework approach. RESULTS: Difficulty establishing causes and differentiating between prostate and bladder symptoms were key challenges to the diagnosis of LUTS in primary care, often making treatment a process of trial and error. Pharmacological treatments were commonly ineffective and often caused side effects. Despite this, patients were generally satisfied with GP consultations and expressed a preference for treatment in primary care. CONCLUSION: Managing LUTS in primary care is a more accessible option for patients. Given the challenges of LUTS diagnosis, an effective diagnostic tool for use by GPs would be beneficial. Ensuring bothersome LUTS are not dismissed as a normal part of ageing is essential in improving patients' quality of life. Greater exploration of the role of non-pharmacological treatments is needed.

Conducting invasive urodynamics in primary care: qualitative interview study examining experiences of patients and healthcare professionals.

BACKGROUND: Invasive urodynamics is used to investigate the causes of lower urinary tract symptoms; a procedure usually conducted in secondary care by specialist practitioners. No study has yet investigated the feasibility of carrying out this procedure in a non-specialist setting. Therefore, the aim of this study was to explore, using qualitative methodology, the feasibility and acceptability of conducting invasive urodynamic testing in primary care. METHODS: Semi-structured interviews were conducted during the pilot phase of the PriMUS study, in which men experiencing bothersome lower urinary tract symptoms underwent invasive urodynamic testing along with a series of simple index tests in a primary care setting. Interviewees were 25 patients invited to take part in the PriMUS study and 18 healthcare professionals involved in study delivery. Interviews were audio-recorded, transcribed verbatim and analysed using a framework approach. RESULTS: Patients generally found the urodynamic procedure acceptable and valued the primary care setting due to its increased accessibility and familiarity. Despite some logistical issues, facilitating invasive urodynamic testing in primary care was also a positive experience for urodynamic nurses. Initial issues with general practitioners receiving and utilising the results of urodynamic testing may have limited the potential benefit to some patients. Effective approaches to study recruitment included emphasising the benefits of the urodynamic test and maintaining contact with potential participants by telephone. Patients' relationship with their general practitioner was an important influence on study participation. CONCLUSIONS: Conducting invasive urodynamics in primary care is feasible and acceptable and has the potential to benefit patients. Facilitating study procedures in a familiar primary care setting can impact positively on research recruitment. However, it is vital that there is a support network for urodynamic nurses and expertise available to help interpret urodynamic results.

Three distinct clades of cultured heterocystous cyanobacteria constitute the dominant N2-fixing members of biological soil crusts of the Colorado Plateau, USA.

The identity of the numerically dominant N(2)-fixing bacteria in biological soil crusts of the Colorado Plateau region and two outlying areas was determined using multiple approaches, to link the environmental diversity of nifH gene sequences to cultured bacterial isolates from the regions. Of the nifH sequence-types detected in soil crusts of the Colorado Plateau, 89% (421/473) were most closely related to nifH signature sequences from cyanobacteria of the order Nostocales. N(2)-fixing cyanobacterial strains were cultured from crusts and their morphotypes, 16S rRNA gene and nifH gene sequences were characterized. The numerically dominant diazotrophs in the Colorado Plateau crusts fell within three clades of heterocystous cyanobacteria. Two clades are well-represented by phylogenetically and morphologically coherent strains, corresponding to the descriptions of Nostoc commune and Scytonema hyalinum, which are widely recognized as important N(2)-fixing components of soil crusts. A third, previously-overlooked clade was represented by a phylogenetically coherent but morphologically diverse group of strains that encompass the morphogenera Tolypothrix and Spirirestis. Many of the strains in each of these groups contained at least two nifH copies that represent different clusters in the nifH environmental survey.

Acidobacteria phylum sequences in uranium-contaminated subsurface sediments greatly expand the known diversity within the phylum.

The abundance and composition of bacteria of the phylum Acidobacteria were surveyed in subsurface sediments from uranium-contaminated sites using amplification of 16S rRNA genes followed by clone/sequence analysis. Analysis of sequences from this study and public databases produced a revised and greatly expanded phylogeny of the Acidobacteria phylum consisting of 26 subgroups.