Concomitant use of oral anticoagulants in patients with advanced prostate cancer receiving apalutamide: A post-hoc analysis of TITAN and SPARTAN studies

Apalutamide, an androgen receptor signaling inhibitor, in combination with androgen-deprivation therapy (ADT), is approved for treatment of patients with nonmetastatic castration-resistant prostate cancer and metastatic castration-sensitive prostate cancer, based on the data from the phase 3 SPARTAN and TITAN studies respectively. Apalutamide is an inducer of cytochrome P450 enzymes and P-glycoprotein, which are involved in the metabolism of oral anticoagulants (OACs) and may thus have potential drug-drug interactions when co-administered with OACs. Concomitant use of certain OACs such as apixaban, rivaroxaban, edoxaban, dabigatran, and warfarin was allowed in the SPARTAN and TITAN studies. A post-hoc analysis was conducted to evaluate the incidence of treatment-emergent thrombotic and embolic adverse events (AEs) in patients receiving concomitant OACs with apalutamide + ADT or placebo + ADT in both the studies. Anticoagulants were identified by WHO Drug Anatomical Therapeutic Chemical level 4 classifications. Thrombotic and embolic AEs were coded using the Medical Dictionary for Regulatory Activities Version 22.1. Data were analyzed from patients receiving concurrent OACs among all treated patients in SPARTAN (apalutamide + ADT: 95/803 [11.8%]; placebo + ADT: 48/398 [12.1%]) and TITAN (apalutamide + ADT: 31/524 [5.9%]; placebo + ADT: 28/527 [5.3%]). No consequential differences were observed in the occurrence of thrombotic and embolic events between apalutamide + ADT and placebo + ADT groups receiving concomitant OACs in SPARTAN (11.6% vs 12.5%) or TITAN (19.4% vs 21.4%). Grade 3/4 thrombotic and embolic AEs observed in patients receiving concomitant OACs with apalutamide + ADT or placebo + ADT were 6 (6.3%) vs 5 (10.4%) in SPARTAN and 3 (9.7%) vs 1 (3.6%) in TITAN. This analysis suggests that when necessary, concomitant OACs can be used with apalutamide with appropriate monitoring.     

TEMPO-oxidised nanocellulose hydrogels and self-standing films derived from bacterial cellulose nanopaper

Hydrogels derived from TEMPO-oxidised cellulose nanofibrils (TOCNs) are not robust and inherently water unstable if the TOCNs are not crosslinked or coated with a water-swellable polymer. Furthermore, the manufacturing of self-standing TOCN films is still a challenge due to the small TOCN diameter and the viscosifying effect of TOCNs. Here, we report the TEMPO-mediated oxidation of bacterial cellulose (BC) nanopaper as a route to produce robust and water stable TOCN hydrogels without the need of additional additives or crosslinking steps. Pristine BC pellicle was first press-dried into a dried and well-consolidated BC nanopaper, followed by TEMPO-oxidation at various NaClO concentrations. The oxidation reaction introduced carboxylate moieties onto the exposed BC nanofibrils within the nanopaper network structure. This then led to the expansion and swelling of the nanopaper into a hydrogel. A swelling ratio of up to 100 times the original thickness of the BC nanopaper was observed upon TEMPO-oxidation. The water retention value of the TEMPO-oxidised BC hydrogels was also found to increase with increasing carboxylate content. These TEMPO-oxidised BC hydrogels were found to be robust and water-stable, even under prolonged (>1 month) magnetic stirring in water. We further showed that high grammage self-standing TOCN films (100 g m⁻²) can be fabricated as simple as press-drying these water stable TEMPO-oxidised BC hydrogels without the need of vacuum-assisted filtration or slow-drying, which is typically the rate-limiting step in the manufacturing of TOCN films.

TEMPO-mediated oxidation of well-consolidated bacterial cellulose (BC) nanopaper derived from pristine BC pellicle as a route to produce robust and water stable nanocellulose hydrogels.     

ALPPS Offers a Better Chance of Complete Resection in Patients with Primarily Unresectable Liver Tumors Compared with Conventional-Staged Hepatectomies: Results of a Multicenter Analysis

Background

Portal vein occlusion to increase the size of the future liver remnant (FLR) is well established, using portal vein ligation (PVL) or embolization (PVE) followed by resection 4–8 weeks later. Associating liver partition with portal vein ligation for staged hepatectomy (ALPPS) combines PVL and complete parenchymal transection, followed by hepatectomy within 1–2 weeks. ALPPS has been recently introduced but remains controversial. We compare the ability of ALPPS versus PVE or PVL for complete tumor resection.

Methods

A retrospective review of all patients undergoing ALPPS or conventional staged hepatectomies using PVL or PVE at four high-volume HPB centres between 2003 and 2012 was performed. Patients with primary liver tumors and liver metastases were included. Primary endpoint was complete tumor resection. Secondary endpoints include 90-day mortality, complications, FLR increase, time to resection, and tumor recurrence.

Results

Forty-eight patients with ALPPS were compared with 83 patients with conventional-staged hepatectomies. Eighty-three percent (40/48 patients) of ALPPS patients achieved complete resection compared with 66 % (55/83 patients) in PVE/PVL (odds ratio 3.34, p = 0.027). Ninety-day mortality in ALPPS and PVE/PVL was 15 and 6 %, respectively (p = 0.2). Extrapolated growth rate was 11 times higher in ALPPS (34.8 cc/day; interquartile range (IQR) 26–49) compared with PVE/PVL (3 cc/day; IQR2-6; p = 0.001). Tumor recurrence at 1 year was 54 versus 52 % for ALPPS and PVE/PVL, respectively (p = 0.7).

Conclusions

This study provides evidence that ALPPS offers a better chance of complete resection in patients with primarily unresectable liver tumors at the cost of a high mortality. The technique is promising but should currently not be used outside of studies and registries.     

A Novel Bayesian Method for Efficacy Assessment in Animal Oncology Studies

In pre-clinical oncology studies, the investigator often compares efficacy of two or more treatments on tumor-bearing animals over a period of time. This is accomplished either through comparison of tumor volumes at various time points or overall survival. Due to ethical concerns, animals are euthanized before the end of the study whenever their tumor volumes reach a prespecified limit, the loss of bodyweight is beyond 20% or severely ulcerated tumors are observed. The traditional cross time-point tumor-size comparisons should not be performed when animals leave the study in a nonrandom nature. Survival analysis may alternatively be carried out to compare the time-to-euthanasia or natural death across treatment groups. As a result of government regulations, however, animal survival studies are hampered by small-sample sizes, often making statistical inference of survival data difficult. For example, it may be impossible to estimate median survival for an efficacious treatment group in which the majority of animals survive to the end of the study. Such cases create challenges to investigators who wish to rank-order the treatment effects, in effect picking the “winners” for further investigation. In this aricle, we list the benefits and shortcomings of popular methods and then propose a novel hypothesis test based directly on the survival probability to rank order the efficacy of treatments. The performance of the method is illustrated using a real-life example.     

新生儿远程医疗

正医生短缺是一个世界性的问题。最近,世界卫生组织(WHO)报告全球短缺430万名医生、护士和其他卫生保健专业人员。在发展中国家,由于医学院的数量和能力有限,这种短缺更加严重。包括美国、加拿大、新西兰、英国、澳大利亚和德国在内的许多发达国家都报告了类似的问题~([1])。美国医学院协会估计,到2032年,美国医生缺口将达到46 900～121 900人~([2])。医生短缺将导致城市和农村地区都得不到足够的医疗。目前,城市地区每万名居民医生的数量是农村地区的两倍。在亚专科医