bluuebunny/crossref_metadata_2025_split huggingface dataset:
Trends in mechanical ventilation: are we ventilating our patients in the best possible way?
Authors: Dellaca’ Raffaele L. , Veneroni Chiara , Farre’ Ramon 
Published: July 2017

This review addresses how the combination of physiology, medicine and engineering principles contributed to the development and advancement of mechanical ventilation, emphasising the most urgent needs for improvement and the most promising directions of future development.Several aspects of mechanical ventilation are introduced, highlighting on one side the importance of interdisciplinary research for further development and, on the other, the importance of training physicians sufficiently on the technological aspects of modern devices to exploit properly the great complexity and potentials of this treatment.Educational aimsTo learn how mechanical ventilation developed in recent decades and to provide a better understanding of the actual technology and practice.To learn how and why interdisciplinary research and competences are necessary for providing the best ventilation treatment to patients.To understand which are the most relevant technical limitations in modern mechanical ventilators that can affect their performance in delivery of the treatment.To better understand and classify ventilation modes.To learn the classification, benefits, drawbacks and future perspectives of automatic ventilation tailoring algorithms.
Treating symptomatic uterine fibroids with myomectomy: current practice and views of UK consultants
Authors: Sirkeci R. Fusun , Belli Anna Maria , Manyonda Isaac T. 
Published: July 2017

Abstract
Background
The demand for uterus-sparing treatments is increasing as more women postpone childbirth to their 30–40s, when fibroids are more symptomatic. With an increasing choice of treatment options and changing care-provider profiles, now is an opportune time to survey current practices and opinions. Using a 25-stem questionnaire, a web-based survey was used to capture the practices and opinions of UK consultant gynecologists on the treatment of symptomatic fibroids, including the types of procedure most frequently used, methods used to reduce blood loss, and awareness and acceptability of treatment options, and to assess the impact of gender and experience of the treating gynecologist.

Results
The response rate was 22%. Laparascopic myomectomy is used least frequently, with 80% of the respondents using GnRHa preoperatively to minimize blood loss and correct anemia, while vasopressin is most frequently used to reduce intraoperative blood loss. Female consultants operate significantly less frequently than males. Those with more than 10 years consultant experience are more likely to perform an open myomectomy compared to those with less than 10 years experience.

Conclusions
Compared to a similar survey performed 10 years ago, surgical methods remain to be the most common treatments, but use of less invasive treatments such as UAE has increased. Consultants’ attitudes appear to be responding to the patient demand for less radical treatments. However, it is yet to be seen if the changing consultant demographics will keep up with this demand. The low response rate warrants cautious interpretation of the results, but they provide an interesting snapshot of current views and practices.
Mortality gap for people with bipolar disorder and schizophrenia: UK-based cohort study 2000–2014
Authors: Hayes Joseph F. , Marston Louise , Walters Kate , King Michael B. , Osborn David P. J. 
Published: July 2017

BackgroundBipolar disorder and schizophrenia are associated with increased mortality relative to the general population. There is an international emphasis on decreasing this excess mortality.AimsTo determine whether the mortality gap between individuals with bipolar disorder and schizophrenia and the general population has decreased.MethodA nationally representative cohort study using primary care electronic health records from 2000 to 2014, comparing all patients diagnosed with bipolar disorder or schizophrenia and the general population. The primary outcome was all-cause mortality.ResultsIndividuals with bipolar disorder and schizophrenia had elevated mortality (adjusted hazard ratio (HR) = 1.79, 95% CI 1.67–1.88 and 2.08, 95% CI 1.98–2.19 respectively). Adjusted HRs for bipolar disorder increased by 0.14/year (95% CI 0.10–0.19) from 2006 to 2014. The adjusted HRs for schizophrenia increased gradually from 2004 to 2010 (0.11/year, 95% CI 0.04–0.17) and rapidly after 2010 (0.34/year, 95% CI 0.18–0.49).ConclusionsThe mortality gap between individuals with bipolar disorder and schizophrenia, and the general population is widening.
Occurrence of ALK fusions in cancers other than non-small cell lung cancer in a wide variety of tumor types and response to anti-ALK targeted therapy.
Authors: Ross Jeffrey S. , Ali Siraj Mahamed , Elvin Julia Andrea , Schrock Alexa Betzig , Suh James , Vergilio Jo-Anne , Ramkissoon Shakti , Severson Eric Allan , Daniel Sugganth , Fabrizio David , Frampton Garrett Michael , Miller Vincent A. , Stephens Philip J. , Gay Laurie M. 
Published: July 2017

11595 Background: Genomic fusions of the anaplastic lymphoma kinase gene ( ALK) are an established therapy target for patients with non-small cell lung cancer (NSCLC), but are not well-characterized in non-NSCLC malignancies. Methods: Comprehensive genomic profiling (CGP) of 92,784 clinically advanced malignancies was performed using a hybrid-capture, adaptor ligation based NGS assay to a mean coverage depth of >600X. Tumor mutational burden (TMB) was calculated from a minimum of 1.1 Mb of sequenced DNA. Results: 17,127/92,784 (18.5%) were NSCLC and 75,657 (81.5%) were non-NSCLC. Of the 697 (0.8%) of cases with ALK fusions, 554 (79%) were identified in NSCLC and 143 (21%) in non-NSCLC including 67 carcinomas; 39 sarcomas including 30 non-uterine and uterine leiomyosarcomas and inflammatory myofibroblastic tumors; 24 in hematolymphoid malignancies including non-Hodgkins lymphomas, myelomas and histiocytic malignancies; 3 in gliomas; 2 each in mesotheliomas, neuroblastomas and undifferentiated malignancies and 1 in melanoma. ALK fusions were significantly more frequently identified in NSCLC (3.2%) than in non-NSCLC (p<0.0001). The non-NSCLC ALK fusion positive patients were significantly older (p<0.0001) and more often female (p<0.0001) than the NSCLC ALK fusion positive patients. At 84%, the more frequent finding of EML4 as the fusion partner in the NSCLC patients versus non-NSCLC patients at 31% was significant (p<0.0001). ALK fusion positive non-NSCLC had significantly lower TMB (mean 5.01 mutations/Mb) than non- ALK altered non-NSCLC (p=0.006). Non-NSCLC ALKfusion positive cases responding to ALK inhibitors will be presented. Conclusions: In non-NSCLC patients ALK fusions are rare and found in both epithelial and mesenchymal malignancies. Initial evidence strongly suggests that anti-ALK therapies can be effective in ALK fusion driven non-NSCLC .
Molecular landscape of BRAF mutations in large cell neuroendocrine carcinoma of lung: An analysis of BRAF mutations and a case report of a BRAF non-V600E mutated tumor responding to targeted therapy.
Authors: Tamragouri Keerthi , Chae Young Kwang , Chung Jon , Miller Vincent A. , Ali Siraj Mahamed , Giles Francis J. 
Published: July 2017

11621 Background: In advanced stages, large cell neuroendocrine carcinoma of the lung (L-LCNEC) mimics small cell lung cancer (SCLC) despite its traditional classification as a non-small cell lung cancer (NSCLC). Here we present a focused analysis of BRAF mutations in this population. Methods: Comprehensive genomic profiling of tumor tissues was performed from a cohort of 300 patients with biopsy proven L-LCNEC. Specimens were either from a primary lung lesion or metastatic site. Results: 14 unique BRAF alterations (amplifications, mutations) were identified in 13 patients. The importance of biomarker driven therapy is subsequently highlighted with our case of a 69 year-old male diagnosed with metastatic L-LCNEC that did not respond to cisplatin/etoposide. He then demonstrated a significant durable response with therapy targeted toward a BRAF non-V600E mutation (G469R) associated with biomarker response identified through circulating cell free tumor DNA analysis. A change in clonal allele frequency from nearly 50% to non-detectable was observed. Conclusions: Though uncommon, L-LCNEC does appear to contain activating and therefore actionable alterations. We thus highlight the value of pursuing NGS for these patients. [Table: see text]
The age specific genomic landscape of cancer.
Authors: Connelly Caitlin F. , Severson Eric Allan , Lieu Christopher Hanyoung , Meyer Joshua E. , Stephens Phil , Frampton Garrett Michael 
Published: July 2017

1568 Background: The frequency of genomic alterations in cancer is known to differ based on a patient’s age. Many studies have characterized the genomic characteristics of pediatric cancers; however, less is known about how the genomic landscape of mutations changes with age in adult patients. Accurately characterizing these differences will help guide personalized treatment strategies and illuminate differences in the genetic etiology of cancer at different ages of onset. Methods: Comprehensive genomic profiling was performed on > 100,000 patients in the course of routine care for patients with predominantly relapsed, refractory or metastatic cancer. For 117 types of cancer with ≥ 100 cases, logistic regression was used to identify genomic features with statistically significant dependence on patient age. Results: Many known associations with age were identified, including increased prevalence of BRCA1/2 mutations in younger breast and ovarian cancer patients and increased prevalence of mismatch repair mutations in younger colorectal and endometrial adenocarcinoma patients. In lung adenocarcinoma, we identified 19 genes for which alteration prevalence was significantly associated with patient age. The genes ALK, ROS1, and RET were more commonly altered in younger patients, KRAS and MET were altered more frequently in older patients, and TP53 was most frequently altered at intermediate ages (40-60). Interestingly, a set of genes that have previously been associated with clonal hematopoiesis (CH) were found to be more frequently detected in older patients across a wide variety of cancer types. Based on the statistical power provided by this large cohort, several novel age based differences in gene alteration rates across multiple tumor types were detected and will be presented. Conclusions: Clear differences in genomics based on patient age were observed. This methodology can be used to identify novel associations between germline alterations and cancer types and somatic alterations that occur predominantly in young or elderly patients. These results also highlight the importance of accurately identifying and properly reporting somatic CH mutations during tumor genomic profiling.
Development and validation of a real-world clinicogenomic database.
Authors: Singal Gaurav , Miller Peter Grant , Agarwala Vineeta , He Jie , Gossai Anala , Frank Shannon , Bourque David , Bowser Bryan , Caron Thomas , Baydur Ezra , Seidl-Rathkopf Kathi , Ivanov Ivan , Parker Alex , Guria Ameet , Frampton Garrett Michael , Jaskiw Ann , Feuchtbaum Dana , Nussbaum Nathan Coleman , Abernethy Amy Pickar , Miller Vincent A. 
Published: July 2017

2514 Background: Genomic findings have diagnostic, prognostic, and predictive utility in clinical oncology. Population studies have been limited by reliance on trials, registries, or institutional chart review, which are costly and represent narrow populations. Integrating electronic health record (EHR) and genomic data collected as part of routine clinical practice may overcome these hurdles. Methods: Patients in the Flatiron Health Database with non-small cell lung cancer (NSCLC) who underwent comprehensive genomic profiling (CGP) by Foundation Medicine were included. EHR processing included structured data harmonization and abstraction of variables from unstructured documents. EHR and CGP data were de-identified and linked in a HIPAA-compliant process. Data included clinical characteristics, alterations across > 300 genes, tumor mutation burden (TMB), therapies and associated real-world responses, progression, and overall survival (OS). Results: The cohort (n = 1619) had expected clinical (mean age 66; 75% with smoking hx; 80% non-squamous) and genomic (18% EGFR; 4% ALK; 1% ROS1) properties of NSCLC. Presence of a driver mutation (EGFR, ALK, ROS1, MET, BRAF, RET, or ERBB2; n = 576) was associated with younger age, female gender, non-smoking, improved OS (35 vs 19 mo, LR p < 0.0001), and prolonged survival when treated with NCCN-recommended therapy (42 vs 28 mo, LR p = 0.001). CGP identified false negative results in up to 30% of single-biomarker tests for EGFR, ALK, and ROS1. CGP accuracy was supported by clinical outcomes. For example, 5 patients with prior negative ALK-fusion testing began ALK-directed therapy after positive CGP results. All 5 exhibited at least a partial response as recorded in the EHR by treating clinicians. Immunotherapy was used in 22% of patients (n = 353). TMB predicted response to nivolumab, including in PD-L1 negative populations. We recapitulated known associations with smoking, histology, and driver mutations. Conclusions: We present and validate a new paradigm for rapidly generating large, research-grade, longitudinal clinico-genomic databases by linking genomic data with EHR clinical annotation. This method offers a powerful tool for understanding cancer genomics and advancing precision medicine.
Targeted therapy for HER2 driven colorectal cancer.
Authors: Ross Jeffrey S. , Ali Siraj Mahamed , Elvin Julia Andrea , Schrock Alexa Betzig , Suh James , Vergilio Jo-Anne , Ramkissoon Shakti , Severson Eric Allan , Daniel Sugganth , Fabrizio David , Frampton Garrett Michael , Miller Vincent A. , Stephens Philip J. , Gay Laurie M. 
Published: July 2017

3583 Background: ERBB2 ( HER2) genomic alterations (GA) are evolving therapy taregets in metastatc coorectal cancer (mCRC). Methods: Hybrid capture based comprehensive genomic profiling (CGP) was performed on 8874 (9.6%) mCRC including both colonic adenocarcinomas (7587 cases; 85%) and rectal adenocarcinomas (1287 cases, 15%) Tumor mutational burden (TMB) was calculated from a minimum of 1.2 Mb of sequenced DNA. Results: ERBB2 amplifications or a short variant (SV) alterations or both were found in 433 (4.9%) of the total mCRC. 195 (45%) of the ERBB2 positive mCRC were female and 238 (55%) were male. Median age was 54 years (range 22 to 88 years). The most frequently co-altered genes were SV GA in TP53 (82%), APC (70%), KRAS (26%), SMAD4 (15%) and PIK3CA (13%). Clinically relevant GA significantly under-represented in ERBB2-altered CRC included significantly reduced GA in KRAS at 26% (p = 0.001) and BRAF at 4% (p = 0.003) as well as other kinases at 1% including EGFR, KIT, MET and RET. The frequency of TMB at > 10 mut/Mb (p < 0.0001), but at > 20 mut/Mb mCRC cases demonstrated virtually the same results regardless to ERBB2 status at a frequency of x%. The overall ERBB2 GA frequency at 5.3% in rectal mCRC is slightly higher than that seen in colonic mCRC at 4.9%, (p = 0.36). The frequency of TMB > 10 mut/Mb in ERBB2 WT mCRC is greater in the colonic mCRC than the rectal mCRC (p < 0.0001 for both comparisons). When > 20 mut/Mb is used as the cut-off, the greater frequency of TMB in colonic mCRC versus rectal mCRC remains significant (p < 0.0001). When the ERBB2altered mCRC cases are evaluated, the greater frequency of TMB > 10 mu/Mb in colonic mCRC versus rectal mCRC remains significant (p = 0.009), but the greater frequency in colonic verses rectal mCRC at the > 20 mut/Mb is not significant (p = 0.37). Conclusions: Although lower than observed in breast and upper gastrointestinal carcinomas where anti-HER2 therapies are approved indications, the frequency of ERBB2 GA in CRC at 4.9% is significant. Importantly, nearly half of CRC ERBB2 alterations are SVs, not detectable by routine IHC and FISH testing. However, the success of anti-HER2 therapies shown here and progress in on-going clinical trials indicates that targeting ERBB2 has potential to become an approved advance in precision therapy for mCRC patients.
Genomic profiling of circulating tumor DNA (ctDNA) from patients (pts) with pancreatic ductal adenocarcinoma (PDA).
Authors: Bahary Nathan , He Jie , Bailey Mark , Zhong Shan , Li Gerald , Young Lauren , Singhi Aatur D. , Stephens Phil , Ali Siraj Mahamed , Singal Gaurav , Schrock Alexa Betzig , Chung Jon , Ross Jeffrey S. , Miller Vincent A. , George Ben 
Published: July 2017

4128 Background: PDA is a lethal and increasingly common malignancy and tissue samples for genomic characterization may be limited. As PDA has a high and consistent frequency of KRAS, p53 and CDKN2A mutations it serves as a robust indication to test the utility of ctDNA in accurately characterizing genomic alterations (GA). A prior study suggested significant differences between ctDNA and tissue base profiling but assays were not conducted on the same platform (PMID27833075). We undertook this study to see whether ctDNA could recapitulate the known genomic hallmarks of tumor based profiling. Methods: Hybrid-capture based genomic profiling of 62 genes (FoundationACT) was performed on ctDNA from 78 pts with advanced PDA with samples received in the course of clinical care. The fraction of ctDNA in the blood was estimated using the maximum somatic allele frequency (MSAF) for each sample. Frequencies of alterations in these common drivers were then compared to those seen in tumors of pts who underwent comprehensive genomic profiling (CGP) tissue testing performed on the same core platform, FoundationOne, and The Cancer Genome Atlas (TCGA). Results: Pt characteristics: Median age 65 (range, 47-88); Female (33) /Male (45). FoundationACT results show that 53/78 (68%) cases had MSAF >0 (56%-78%%, 95% CI). ≥1 GA was reported in 81% of the cases with evidence of ctDNA in the blood. The most common GA detected by FoundationACT (based on cases with evidence of ctDNA in blood) vs FoundationOne were in KRAS (59% vs 89%, p< 0.0001), TP53 (69% vs.74%, p=0.19), and CDKN2A (14% vs.45%). Other detected clinically relevant GA detected by FoundationACT included: BRCA1, ERBB2, NF1, PIK3CA. Conclusions: This study demonstrates significant differences between the established driver oncogenic alterations for PDA, as assessed by ct DNA and tissue based genomic profiling which are unlikely to be explained by differences in assay, but rather novel cancer biology. At present use of ctDNA genomic profiling in PDA should not routinely replace tissue based genomic characterization. [Table: see text]
Comprehensive genomic profiling (CGP) versus conventional molecular diagnostic testing of patients with advanced non-small cell lung cancer (NSCLC): Overall survival (OS) and cost in a U.S. health plan population.
Authors: Signorovitch James , Zhou Zhou , Ryan Jason , Chawla Anita 
Published: July 2017

6599 Background: Molecular diagnostic testing options in NSCLC include conventional testing (specific alterations in single genes or multi-gene panels), and CGP (all classes of genomic alterations—base pair substitutions, copy number, insertions/deletions, and rearrangements in multi-gene panels). Guidelines recommend broad molecular profiling to enable genomic matching with available compendia-based and investigational treatment options. This study estimated the incremental benefits and costs of CGP versus conventional testing of patients with advanced NSCLC. Methods: The impacts of increased use of CGP (via FoundationOne) versus conventional molecular testing on OS and on a commercial US health plan budget were estimated using a decision-analytic model. The number of patients needed to test with CGP to add 1 life year was also estimated. Model inputs were based on published literature (incidence rates, OS associated with drugs indicated for advanced NSCLC), real-world data (testing rates, and biopsy, conventional testing, and medical service costs from administrative claims data analyses), list price of FoundationOne, and assumptions for clinical trial participation. Results: Among 2 million covered lives, an estimated 532 had advanced NSCLC and 266 received molecular diagnostic testing. An increase in CGP use from 2% to 10% (+21 patients receiving CGP) was associated with +2 years in population OS and a budget impact of $0.018 per member per month (PMPM). The budget impact was primarily attributable to changes in drug use, longer treatment, and longer survival (collectively $0.013 PMPM) with the remainder due to CGP cost ($0.005 PMPM). Approximately 11 patients need to be tested with CGP versus conventional molecular diagnostic testing to add 1 life year. Conclusions: An increase in molecular diagnostic testing with CGP versus conventional testing to inform treatment decisions in patients with advanced NSCLC was associated with a gain in OS and a modest health plan budget impact, with most of the added costs attributable to increased use of effective treatments and prolonged survival.
Estimated cost of anticancer therapy directed by comprehensive genomic profiling (CGP) in a single-center study.
Authors: Signorovitch James , Janku Filip , Wheler Jennifer J. , Miller Vincent A. , Ryan Jason , Zhou Zhou , Chawla Anita 
Published: July 2017

6605 Background: Accumulating evidence supports the clinical benefit of targeted therapies matched to cancer patients based on genomic alterations. CGP, which detects all classes of alterations (base pair substitutions, copy number, insertions/deletions, and rearrangements), can match more patients with available and investigational therapies. This study estimated anti-cancer drug costs and overall survival (OS) for matched vs. unmatched therapy. Methods: Costs were estimated for patients with complete data (N = 188/500) from a prospective, nonrandomized, phase I oncology center study of patients with diverse refractory cancers who underwent CGP and were treated with matched or unmatched therapy (PMID: 27197177). Average time to treatment failure and average OS were assessed during the observation period. Patient-specific drug and administration costs were imputed for the first regimen after CGP based on drug classes, unit costs, and times to treatment failure. Results: Patients onmatched (N = 122) vs. unmatched (N = 66) therapy had, on average, longer time on treatment (+1.5 mos), longer observed survival (+2.4 mos), and higher anti-cancer drug costs (+$38K) (all p < 0.01); 66% of increased drug costs were attributable to longer time on treatment as opposed to higher monthly drug costs. Combination therapy was used for 71% of matched and 53% of unmatched patients. Those undergoing CGP in earlier-line (1-3; N = 58) vs. later-line (4+; N = 130) therapy had numerically larger incremental increases in average times on treatment (+1.9 vs. +1.2 mos) and survival (+2.5 vs. +2.1 mos), and numerically lower incremental drug costs (+$27K vs. +$43K), with matched vs. unmatched therapy. Conclusions: For patients cared for in a phase I clinic, matched vs. unmatched therapy was associated with longer treatment durations, longer survival times, and manageable incremental costs. Despite frequent use of combination therapy, most of the increased costs of matched therapy were due to longer treatment times rather than higher monthly drug costs. Benefits of matching were numerically greater in earlier- vs. later-lines, consistent with the value of earlier-line use of CGP to guide treatment.