Outcomes and risk score for distal pancreatectomy with celiac axis resection (DP-CAR) : an international multicenter analysis

Background: Distal pancreatectomy with celiac axis resection (DP-CAR) is a treatment option for selected patients with pancreatic cancer involving the celiac axis. A recent multicenter European study reported a 90-day mortality rate of 16%, highlighting the importance of patient selection. The authors constructed a risk score to predict 90-day mortality and assessed oncologic outcomes. Methods: This multicenter retrospective cohort study investigated patients undergoing DP-CAR at 20 European centers from 12 countries (model design 2000-2016) and three very-high-volume international centers in the United States and Japan (model validation 2004-2017). The area under receiver operator curve (AUC) and calibration plots were used for validation of the 90-day mortality risk model. Secondary outcomes included resection margin status, adjuvant therapy, and survival. Results: For 191 DP-CAR patients, the 90-day mortality rate was 5.5% (95 confidence interval [CI], 2.2-11%) at 5 high-volume (1 DP-CAR/year) and 18% (95 CI, 9-30%) at 18 low-volume DP-CAR centers (P=0.015). A risk score with age, sex, body mass index (BMI), American Society of Anesthesiologists (ASA) score, multivisceral resection, open versus minimally invasive surgery, and low- versus high-volume center performed well in both the design and validation cohorts (AUC, 0.79 vs 0.74; P=0.642). For 174 patients with pancreatic ductal adenocarcinoma, the R0 resection rate was 60%, neoadjuvant and adjuvant therapies were applied for respectively 69% and 67% of the patients, and the median overall survival period was 19months (95 CI, 15-25months). Conclusions: When performed for selected patients at high-volume centers, DP-CAR is associated with acceptable 90-day mortality and overall survival. The authors propose a 90-day mortality risk score to improve patient selection and outcomes, with DP-CAR volume as the dominant predictor

Genomic characterization of biliary tract cancers identifies driver genes and predisposing mutations

Background & Aims Biliary tract cancers (BTCs) are clinically and pathologically heterogeneous and respond poorly to treatment. Genomic profiling can offer a clearer understanding of their carcinogenesis, classification and treatment strategy. We performed large-scale genome sequencing analyses on BTCs to investigate their somatic and germline driver events and characterize their genomic landscape. Methods We analyzed 412 BTC samples from Japanese and Italian populations, 107 by whole-exome sequencing (WES), 39 by whole-genome sequencing (WGS), and a further 266 samples by targeted sequencing. The subtypes were 136 intrahepatic cholangiocarcinomas (ICCs), 101 distal cholangiocarcinomas (DCCs), 109 peri-hilar type cholangiocarcinomas (PHCs), and 66 gallbladder or cystic duct cancers (GBCs/CDCs). We identified somatic alterations and searched for driver genes in BTCs, finding pathogenic germline variants of cancer-predisposing genes. We predicted cell-of-origin for BTCs by combining somatic mutation patterns and epigenetic features. Results We identified 32 significantly and commonly mutated genes including TP53 , KRAS , SMAD4 , NF1 , ARID1A , PBRM1 , and ATR , some of which negatively affected patient prognosis. A novel deletion of MUC17 at 7q22.1 affected patient prognosis. Cell-of-origin predictions using WGS and epigenetic features suggest hepatocyte-origin of hepatitis-related ICCs. Deleterious germline mutations of cancer-predisposing genes such as BRCA1 , BRCA2 , RAD51D , MLH1 , or MSH2 were detected in 11% (16/146) of BTC patients. Conclusions BTCs have distinct genetic features including somatic events and germline predisposition. These findings could be useful to establish treatment and diagnostic strategies for BTCs based on genetic information. Lay summary We here analyzed genomic features of 412 BTC samples from Japanese and Italian populations. A total of 32 significantly and commonly mutated genes were identified, some of which negatively affected patient prognosis, including a novel deletion of MUC17 at 7q22.1 . Cell-of-origin predictions using WGS and epigenetic features suggest hepatocyte-origin of hepatitis-related ICCs. Deleterious germline mutations of cancer-predisposing genes were detected in 11% of patients with BTC. BTCs have distinct genetic features including somatic events and germline predisposition

Taxonomy based on science is necessary for global conservation

Peer reviewe

Taxonomy Based on Science Is Necessary for Global Conservation [Formal comment]

Taxonomy is a scientific discipline that has provided the universal naming and classification system of biodiversity for centuries and continues effectively to accommodate new knowledge. A recent publication by Garnett and Christidis expressed concerns regarding the difficulty that taxonomic changes represent for conservation efforts and proposed the establishment of a system to govern taxonomic changes. Their proposal to “restrict the freedom of taxonomic action” through governing subcommittees that would “review taxonomic papers for compliance” and their assertion that “the scientific community\u27s failure to govern taxonomy threatens the effectiveness of global efforts to halt biodiversity loss, damages the credibility of science, and is expensive to society” are flawed in many respects. They also assert that the lack of governance of taxonomy damages conservation efforts, harms the credibility of science, and is costly to society. Despite its fairly recent release, Garnett and Christidis\u27 proposition has already been rejected by a number of colleagues. Herein, we contribute to the conversation between taxonomists and conservation biologists aiming to clarify some misunderstandings and issues in the proposition by Garnett and Christidis. Placing governance over the science of taxonomy blurs the distinction between taxonomy and nomenclature. Garnett and Christidis\u27s proposal is far-reaching but represents a narrow perspective of taxonomy, as utilized by conservation, and reflects an increasingly broad misunderstanding throughout biology of the scientific basis of taxonomy, formalized nomenclature, and the relationship between them. This trend may have resulted from the attenuation of instruction in taxonomic principles and, in particular, nomenclature at many universities, in part because of a shift in research priorities away from taxonomy

Taxonomy based on science is necessary for global conservation

Taxonomy is a scientific discipline that has provided the universal naming and classification system of biodiversity for centuries and continues effectively to accommodate new knowledge. A recent publication by Garnett and Christidis [1] expressed concerns regarding the difficulty that taxonomic changes represent for conservation efforts and proposed the establishment of a system to govern taxonomic changes. Their proposal to “restrict the freedom of taxonomic action” through governing subcommittees that would “review taxonomic papers for compliance” and their assertion that “the scientific community’s failure to govern taxonomy threatens the effectiveness of global efforts to halt biodiversity loss, damages the credibility of science, and is expensive to society” are flawed in many respects. They also assert that the lack of governance of taxonomy damages conservation efforts, harms the credibility of science, and is costly to society. Despite its fairly recent release, Garnett and Christidis\u27 proposition has already been rejected by a number of colleagues [2,3,4,5,6,7,8]. Herein, we contribute to the conversation between taxonomists and conservation biologists aiming to clarify some misunderstandings and issues in the proposition by Garnett and Christidis

Taxonomy Based on Science is Necessary for Global Conservation

Taxonomy is a scientific discipline that has provided the universal naming and classification system of biodiversity for centuries and continues effectively to accommodate new knowledge. A recent publication by Garnett and Christidis (Garnett ST, Christidis L. Taxonomy anarchy hampers conservation. Nature. 2017; 546(7656):25±27. https://doi.org/10.1038/546025a) expressed concerns regarding the difficulty that taxonomic changes represent for conservation efforts and proposed the establishment of a system to govern taxonomic changes. Their proposal to restrict the freedom of taxonomic action through governing subcommittees that would review taxonomic papers for compliance and their assertion that the scientific community\u27s failure to govern taxonomy threatens the effectiveness of global efforts to halt biodiversity loss, damages the credibility of science, and is expensive to society are flawed in many respects. They also assert that the lack of governance of taxonomy damages conservation efforts, harms the credibility of science, and is costly to society. Despite its fairly recent release, Garnett and Christidis\u27 proposition has already been rejected by a number of colleagues. Herein, we contribute to the conversation between taxonomists and conservation biologists aiming to clarify some misunderstandings and issues in the proposition by Garnett and Christidis. Placing governance over the science of taxonomy blurs the distinction between taxonomy and nomenclature. Garnett and Christidis’s proposal is far-reaching but represents a narrow perspective of taxonomy, as utilized by conservation, and reflects an increasingly broad misunderstanding throughout biology of the scientific basis of taxonomy, formalized nomenclature, and the relationship between them. This trend may have resulted from the attenuation of instruction in taxonomic principles and, in particular, nomenclature at many universities, in part because of a shift in research priorities away from taxonomy. Garnett and Christidis assert that an “assumption that species are fixed entities underpins every international agreement on biodiversity conservation.” This assumption demonstrates a fundamental misunderstanding of taxonomy and the evolving view of what species represent. The essential features of science include documenting natural patterns and processes, developing and testing hypotheses, and refining existing ideas and descriptions of nature based on new data and insights. Taxonomy, the science of recognizing and delimiting species, adheres to these fundamental principles. Discoveries of new organisms together with advances in methodology continue unabated, leading to a constant reevaluation of the boundaries between taxonomic entities. Species (and higher taxa) comprise related organisms that may be clustered together differently depending on which sets of criteria are emphasized. Hey et al. acknowledge “the inherent ambiguity of species in nature” but point out that “species-related research and conservation efforts can proceed without suffering from, and without fear of, the ambiguity of species.” Through taxonomic research, our understanding of biodiversity and classifications of living organisms will continue to progress. Any system that restricts such progress runs counter to basic scientific principles, which rely on peer review and subsequent acceptance or rejection by the community, rather than third-party regulation. Thiele and Yeates cautioned that such a system “could lead to authoritarianism and a stifling of innovative taxonomic viewpoints. No other hypothesis-driven field of science would accept such a straitjacket”. Taxonomy and associated nomenclature are not without problems. Even with a common set of facts, alternative interpretations of how to classify organisms can lead to differing classifications. However, the science of taxonomy is increasingly rigorous, which can improve the foundation for targeted legislative action regarding species. Taxonomic instability does not affect all taxonomic groups equally. Garnett and Christidis provide examples from mammals and birds, which collectively represent a small fraction

Practical "1-2-3-4-Day" Rule for Starting Direct Oral Anticoagulants After Ischemic Stroke With Atrial Fibrillation: Combined Hospital-Based Cohort Study

BACKGROUND: The "1-3-6-12-day rule" for starting direct oral anticoagulants (DOACs) in patients with nonvalvular atrial fibrillation after acute ischemic stroke or transient ischemic attack recommends timings that may be later than used in clinical practice. We investigated more practical optimal timing of DOAC initiation according to stroke severity. METHODS: The combined data of prospective registries in Japan, Stroke Acute Management with Urgent Risk-factor Assessment and Improvement-nonvalvular atrial fibrillation (September 2011 to March 2014) and RELAXED (February 2014 to April 2016) were used. Patients were divided into transient ischemic attack and 3 stroke subgroups by the National Institutes of Health Stroke Scale score: mild (0-7), moderate (8-15), and severe (≥16). The early treatment group was defined as patients starting DOACs earlier than the median initiation day in each subgroup. Outcomes included a composite of recurrent stroke or systemic embolism, ischemic stroke, and severe bleeding within 90 days. Six European prospective registries were used for validation. RESULTS: In the 1797 derivation cohort patients, DOACs were started at median 2 days after transient ischemic attack and 3, 4, and 5 days after mild, moderate, and severe strokes, respectively. Stroke or systemic embolism was less common in Early Group (n=785)-initiating DOACS within 1, 2, 3, and 4 days, respectively-than Late Group (n=1012) (1.9% versus 3.9%; adjusted hazard ratio, 0.50 [95% CI, 0.27-0.89]), as was ischemic stroke (1.7% versus 3.2%, 0.54 [0.27-0.999]). Major bleeding was similarly common in the 2 groups (0.8% versus 1.0%). On validation, both ischemic stroke (2.4% versus 2.2%) and intracranial hemorrhage (0.2% versus 0.6%) were similarly common in Early (n=547) and Late (n=1483) Groups defined using derivation data. CONCLUSIONS: In Japanese and European populations, early DOAC initiation within 1, 2, 3, or 4 days according to stroke severity seemed to be feasible to decrease the risk of recurrent stroke or systemic embolism and no increase in major bleeding. These findings support ongoing randomized trials to better establish the optimal timing of DOAC initiation

Outcomes and Risk Score for Distal Pancreatectomy with Celiac Axis Resection (DP-CAR): An International Multicenter Analysis

Background: Distal pancreatectomy with celiac axis resection (DP-CAR) is a treatment option for selected patients with pancreatic cancer involving the celiac axis. A recent multicenter European study reported a 90-day mortality rate of 16%, highlighting the importance of patient selection. The authors constructed a risk score to predict 90-day mortality and assessed oncologic outcomes. Methods: This multicenter retrospective cohort study investigated patients undergoing DP-CAR at 20 European centers from 12 countries (model design 2000–2016) and three very-high-volume international centers in the United States and Japan (model validation 2004–2017). The area under receiver operator curve (AUC) and calibration plots were used for validation of the 90-day mortality risk model. Secondary outcomes included resection margin status, adjuvant therapy, and survival. Results: For 191 DP-CAR patients, the 90-day mortality rate was 5.5% (95 confidence interval [CI], 2.2–11%) at 5 high-volume (≥ 1 DP-CAR/year) and 18% (95 CI, 9–30%) at 18 low-volume DP-CAR centers (P = 0.015). A risk score with age, sex, body mass index (BMI), American Society of Anesthesiologists (ASA) score, multivisceral resection, open versus minimally invasive surgery, and low- versus high-volume center performed well in both the design and validation cohorts (AUC, 0.79 vs 0.74; P = 0.642). For 174 patients with pancreatic ductal adenocarcinoma, the R0 resection rate was 60%, neoadjuvant and adjuvant therapies were applied for respectively 69% and 67% of the patients, and the median overall survival period was 19 months (95 CI, 15–25 months). Conclusions: When performed for selected patients at high-volume centers, DP-CAR is associated with acceptable 90-day mortality and overall survival. The authors propose a 90-day mortality risk score to improve patient selection and outcomes, with DP-CAR volume as the dominant predictor

Highly Efficient Darzens Reactions Mediated by Phosphazene Bases under Mild Conditions

The highly basic and poorly nucleophilic phosphazene base P-1-t-Bu promotes the Darzens condensation of alpha-halo esters with aromatic aldehydes affording alpha,beta-epoxy esters in nearly quantitative yields under mild conditions and in short reaction times. The more basic P-4-t-Bu phosphazene was found useful with low reactivity aldehydes. These reactions can be performed in aprotic organic solvents of low polarity, thus minimizing the hydrolysis of alpha,beta-epoxy esters which often accompanies the base-promoted Darzens condensations