Abstract The aim of this study was to investigate the incidence of bleeding after dental extraction without stopping antiplatelet therapy. Postoperative bleeding was assessed in a total of 1271 ...patients who were divided into two groups: a study group comprising 183 patients on antiplatelet therapy (aspirin 125 patients/185 occasions; clopidogrel 42 patients/65 occasions; dual therapy 16 patients/24 occasions) who underwent 548 dental extractions on 274 occasions, and a control group comprising 1088 patients who were not receiving any antiplatelet or anticoagulant therapy and underwent 2487 dental extractions on 1472 occasions. The incidence of postoperative bleeding was higher in the study group (5/274, 1.8%) than in the control group (10/1472, 0.7%), and also in the dual antiplatelet subgroup (1/24, 4.2%) than in the single antiplatelet subgroups (clopidogrel: 2/65, 3.1%; aspirin: 2/185, 1.1%); however, these differences were not significant. Postoperative bleeding was managed successfully by repacking with Gelfoam impregnated with tranexamic acid powder in 12 patients and by resuturing in three of the control patients undergoing extraction of impacted teeth with flap elevation. These findings indicate that there is no need to interrupt antiplatelet drugs before dental extraction.
Background
The Child–Pugh (CP) score is used widely to assess liver function and predict postoperative outcomes in patients with hepatocellular carcinoma (HCC). Recently, the albumin–bilirubin (ALBI) ...score has been validated as a predictor of overall survival in these patients. This study aimed to compare the ability of the ALBI and CP scores to predict outcomes in patients with HCC after liver resection with curative intent.
Methods
Consecutive patients who underwent liver resection with curative intent for HCC between January 2007 and July 2013 were included in this retrospective study. The performance of the ALBI score in predicting postoperative liver failure (PHLF) and long‐term survival was compared with that of the CP score.
Results
A total of 1242 patients were enrolled. Of these, 166 (13·4 per cent) experienced PHLF. The area under the receiver operating characteristic (ROC) curve of the ALBI score for predicting PHLF was greater than that of the CP score (0·723 versus 0·607; P < 0·001). Similar to findings for CP grade, the incidence and severity of PHLF increased with increasing ALBI grade. The ALBI grade stratified patients into at least two distinct overall survival cohorts (P < 0·001), whereas the CP grade did not. The ALBI grade also classified patients with CP grade A disease into two distinct overall survival cohorts (P < 0·001), and overall survival rates in the group with poorer survival were similar to those in the majority of patients with CP grade B disease. Both CP and ALBI scores had low power in predicting disease‐free survival.
Conclusion
The ALBI grade predicted PHLF and overall survival in patients with HCC undergoing liver resection with curative intent more accurately than the CP grade.
ALBI score may be better
Arginine depletion is a putative target in hepatocellular carcinoma (HCC). HCC often lacks argininosuccinate synthetase, a citrulline to arginine-repleting enzyme. ADI-PEG 20 is a cloned arginine ...degrading enzyme—arginine deiminase—conjugated with polyethylene glycol. The goal of this study was to evaluate this agent as a potential novel therapeutic for HCC after first line systemic therapy.
Patients with histologically proven advanced HCC and Child-Pugh up to B7 with prior systemic therapy, were randomized 2 : 1 to ADI-PEG 20 18 mg/m2 versus placebo intramuscular injection weekly. The primary end point was overall survival (OS), with 93% power to detect a 4–5.6 months increase in median OS (one-sided α = 0.025). Secondary end points included progression-free survival, safety, and arginine correlatives.
A total of 635 patients were enrolled: median age 61, 82% male, 60% Asian, 52% hepatitis B, 26% hepatitis C, 76% stage IV, 91% Child-Pugh A, 70% progressed on sorafenib and 16% were intolerant. Median OS was 7.8 months for ADI-PEG 20 versus 7.4 for placebo (P = 0.88, HR = 1.02) and median progression-free survival 2.6 months versus 2.6 (P = 0.07, HR = 1.17). Grade 3 fatigue and decreased appetite occurred in <5% of patients. Two patients on ADI-PEG 20 had ≥grade 3 anaphylactic reaction. Death rate within 30 days of end of treatment was 15.2% on ADI-PEG 20 versus 10.4% on placebo, none related to therapy. Post hoc analyses of arginine assessment at 4, 8, 12 and 16 weeks, demonstrated a trend of improved OS for those with more prolonged arginine depletion.
ADI-PEG 20 monotherapy did not demonstrate an OS benefit in second line setting for HCC. It was well tolerated. Strategies to enhance prolonged arginine depletion and synergize the effect of ADI-PEG 20 are underway.
www.clinicaltrials.gov (NCT 01287585).
The standard model of injection‐induced seismicity considers changes in Coulomb strength due solely to changes in pore pressure. We consider two additional effects: full poroelastic coupling of ...stress and pore pressure, and time‐dependent earthquake nucleation. We model stress and pore pressure due to specified injection rate in a homogeneous, poroelastic medium. Stress and pore pressure are used to compute seismicity rate through the Dieterich (1994) model. For constant injection rate, the time to reach a critical seismicity rate scales with t ∼ r2/(cfc), where r is distance from the injector, c is hydraulic diffusivity, and fc is a factor that depends on mechanical properties, and weakly on r. The seismicity rate decays following a peak, consistent with some observations. During injection poroelastic coupling may increase or decrease the seismicity rate, depending on the orientation of the faults relative to the injector. If injection‐induced stresses inhibit slip, abrupt shut‐in can lead to locally sharp increases in seismicity rate; tapering the flux mitigates this effect. The maximum magnitude event has been observed to occur postinjection. We suggest the seismicity rate at a given magnitude depends on the nucleation rate, the size distribution of fault segments, and if the background shear stress is low, the time‐varying volume of perturbed crust. This leads to a rollover in frequency‐magnitude distribution for larger events, with a “corner” that increases with time. Larger events are absent at short times, but approach the background frequency with time; larger events occurring post shut‐in are thus not unexpected.
Key Points
Abrupt shut‐in can lead to locally sharp increase in seismicity rate
Tapering injection rate mitigates postinjection increase
In low‐stress environments the largest event may occur postinjection
Messier 87 (M 87) is one of the nearest radio galaxies with a prominent jet extending from sub-pc to kpc scales. Because of its proximity and the large mass of its central black hole (BH), it is one ...of the best radio sources for the study of jet formation. We study the physical conditions near the jet base at projected separations from the BH of ~7–100 Schwarzschild radii (Rsch). Global mm-VLBI Array (GMVA) observations at 86 GHz (λ = 3.5 mm) provide an angular resolution of ~50 μas, which corresponds to a spatial resolution of only 7 Rsch and reach the small spatial scale. We use five GMVA data sets of M 87 obtained from 2004 to 2015 and present new high angular resolution VLBI maps at 86 GHz. In particular, we focus on the analysis of the brightness temperature, the jet ridge lines, and the ratio of jet to counter-jet. The imaging reveals a parabolically expanding limb-brightened jet which emanates from a resolved VLBI core of ~(8–13) Rsch in size. The observed brightness temperature of the core at any epoch is ~(1–3) × 1010 K, which is below the equipartition brightness temperature and suggests magnetic energy dominance at the jet base. We estimate the diameter of the jet at its base to be ~5 Rsch assuming a self-similar jet structure. This suggests that the sheath of the jet may be anchored in the very inner portion of the accretion disk. The image stacking reveals faint emission at the center of the edge-brightened jet on sub-pc scales. We discuss its physical implication within the context of the spine-sheath structure of the jet.
Activation of the phosphatidylinositol-3-kinase (PI3K) pathway via PIK3CA mutations occurs in 28%-46% of hormone receptor-positive (HR+), human epidermal growth factor receptor-2-negative (HER2−) ...advanced breast cancers (ABCs) and is associated with poor prognosis. The SOLAR-1 trial showed that the addition of alpelisib to fulvestrant treatment provided statistically significant and clinically meaningful progression-free survival (PFS) benefit in PIK3CA-mutated, HR+, HER2− ABC.
Men and postmenopausal women with HR+, HER2− ABC whose disease progressed on or after aromatase inhibitor (AI) were randomized 1 : 1 to receive alpelisib (300 mg/day) plus fulvestrant (500 mg every 28 days and once on day 15) or placebo plus fulvestrant. Overall survival (OS) in the PIK3CA-mutant cohort was evaluated by Kaplan–Meier methodology and a one-sided stratified log-rank test was carried out with an O'Brien–Fleming efficacy boundary of P ≤ 0.0161.
In the PIK3CA-mutated cohort (n = 341), median OS 95% confidence interval (CI) was 39.3 months (34.1-44.9) for alpelisib-fulvestrant and 31.4 months (26.8-41.3) for placebo-fulvestrant hazard ratio (HR) = 0.86 (95% CI, 0.64-1.15; P = 0.15). OS results did not cross the prespecified efficacy boundary. Median OS (95% CI) in patients with lung and/or liver metastases was 37.2 months (28.7-43.6) and 22.8 months (19.0-26.8) in the alpelisib-fulvestrant and placebo-fulvestrant arms, respectively HR = 0.68 (0.46-1.00). Median times to chemotherapy (95% CI) for the alpelisib-fulvestrant and placebo-fulvestrant arms were 23.3 months (15.2-28.4) and 14.8 months (10.5-22.6), respectively HR = 0.72 (0.54-0.95). No new safety signals were observed with longer follow-up.
Although the analysis did not cross the prespecified boundary for statistical significance, there was a 7.9-month numeric improvement in median OS when alpelisib was added to fulvestrant treatment of patients with PIK3CA-mutated, HR+, HER2− ABC. Overall, these results further support the statistically significant prolongation of PFS observed with alpelisib plus fulvestrant in this population, which has a poor prognosis due to a PIK3CA mutation.
NCT02437318.
•In SOLAR-1, the key secondary endpoint of OS was evaluated in patients with HR+, HER2−, PIK3CA-mutated ABC.•Adding alpelisib to fulvestrant numerically improved mOS by 7.9 months, though the result was not statistically significant.•OS was numerically improved in hard-to-treat disease, including a 14-month median improvement in those with lung/liver metastases.•Median time to first chemotherapy was delayed by 8.5 months with the addition of alpelisib to fulvestrant.•With longer follow-up the alpelisib plus fulvestrant safety profile was similar to prior reports with no new safety signals.
Advanced ovarian cancer usually spreads to the visceral adipose tissue of the omentum. However, the omental stromal cell-derived molecular determinants that modulate ovarian cancer growth have not ...been characterized. Here, using next-generation sequencing technology, we identify significantly higher levels of microRNA-21 (miR21) isomiRNAs in exosomes and tissue lysates isolated from cancer-associated adipocytes (CAAs) and fibroblasts (CAFs) than in those from ovarian cancer cells. Functional studies reveal that miR21 is transferred from CAAs or CAFs to the cancer cells, where it suppresses ovarian cancer apoptosis and confers chemoresistance by binding to its direct novel target, APAF1. These data suggest that the malignant phenotype of metastatic ovarian cancer cells can be altered by miR21 delivered by exosomes derived from neighbouring stromal cells in the omental tumour microenvironment, and that inhibiting the transfer of stromal-derived miR21 is an alternative modality in the treatment of metastatic and recurrent ovarian cancer.
Dinoflagellate cysts are useful for reconstructing upper water conditions. For adequate reconstructions detailed information is required about the relationship between modern day environmental ...conditions and the geographic distribution of cysts in sediments. This Atlas summarises the modern global distribution of 71 organic-walled dinoflagellate cyst species. The synthesis is based on the integration of literature sources together with data of 2405 globally distributed surface sediment samples that have been prepared with a comparable methodology and taxonomy. The distribution patterns of individual cyst species are being compared with environmental factors that are known to influence dinoflagellate growth, gamete production, encystment, excystment and preservation of their organic-walled cysts: surface water temperature, salinity, nitrate, phosphate, chlorophyll-a concentrations and bottom water oxygen concentrations. Graphs are provided for every species depicting the relationship between seasonal and annual variations of these parameters and the relative abundance of the species. Results have been compared with previously published records; an overview of the ecological significance as well as information about the seasonal production of each individual species is presented.
The relationship between the cyst distribution and variation in the aforementioned environmental parameters was analysed by performing a canonical correspondence analysis. All tested variables showed a positive relationship on the 99% confidence level. Sea-surface temperature represents the parameter corresponding to the largest amount of variance within the dataset (40%) followed by nitrate, salinity, phosphate and bottom-water oxygen concentration, which correspond to 34%, 33%, 25% and 24% of the variance, respectively. Characterisations of selected environments as well as a discussion about how these factors could have influenced the final cyst yield in sediments are included.
► We depict the global distribution of 71 dinocyst species based on 2405 sites. ► Upper water temperature relates most strongly to species distribution. ► Salinity, N, P, chlorophyl-a and bottom O2 vary significantly with distribution. ► We present the environmental characterisation of 71 cyst species. ► We provide information on seasonal cyst production of species when possible.
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