[Prevention and Treatment of Cancer with Vitamin A and Its Derivatives: Cell Differentiation and Proliferation].

Normal differentiation and proliferation of cells are essential for maintaining homeostasis. Following the successful completion of whole genome sequencing, protein modification has been attracted increasing attention in order to understand the roles of protein diversification in protein function and to elucidate molecular targets in mechanisms of signal transduction. Vitamin A is an essential nutrient for health maintenance. It is present as ß-carotene in green and yellow vegetables and retinyl ester in animal products and absorbed into the body from the intestines. After ingestion, it is converted to retinol and oxidized in target cells to retinal, which plays critical roles in vision. It is then further oxidized to retinoic acid (RA), which exhibits a number of effects prior to being metabolized by cytochrome P450 and excreted from the body. Since RA exhibits cell differentiation-inducing actions, it is used as a therapeutic agent for patients with acute promyelocytic leukemia. The current paper describes: (1) HL60 cell differentiation and cell differentiation induction therapy by RA; (2) roles played by RA and retinal and their mechanisms of action; (3) retinoylation, post-translational protein-modified by RA, a novel non-genomic RA mechanism of action without RA receptor; (4) new actions of ß-carotene and retinol in vivo and (5) potent anticancer effects of p-dodecylaminophenol (p-DDAP), a novel vitamin A derivative created from the RA derivative fenretinide. We propose that nutritional management of vitamin A can be effective at preventing and treating diseases, and that p-DDAP is a promising anticancer drug.

EDTA-induced pseudothrombocytopenia in hematopoietic stem cell donor.

We herein report a case of peripheral blood stem cell transplantation (PBSCT) involving a donor with EDTA-induced pseudothrombocytopenia (PTCP). The apheresis product was inspected for 24 h and there was no platelet clumping or thrombocytopenia. In the first 14 months after PBSCT, there has been no transfer of PTCP symptoms.

Examination of aminophenol-containing compounds designed as antiproliferative agents and potential atypical retinoids.

Retinoic acid (RA, 1), an oxidized form of vitamin A, binds to retinoic acid receptors (RAR) and retinoid X receptors (RXR) to regulate gene expression and has important functions such as cell proliferation and differentiation. Synthetic ligands regarding RAR and RXR have been devised for the treatment of various diseases, particularly promyelocytic leukemia, but their side effects have led to the development of new, less toxic therapeutic agents. Fenretinide (4-HPR, 2), an aminophenol derivative of RA, exhibits potent antiproliferative activity without binding to RAR/RXR, but its clinical trial was discontinued due to side effects of impaired dark adaptation. Assuming that the cyclohexene ring of 4-HPR is the cause of the side effects, methylaminophenol was discovered through structure-activity relationship research, and p-dodecylaminophenol (p-DDAP, 3), which has no side effects or toxicity and is effective against a wide range of cancers, was developed. Therefore, we thought that introducing the motif carboxylic acid found in retinoids, could potentially enhance the anti-proliferative effects. Introducing chain terminal carboxylic functionality into potent p-alkylaminophenols significantly attenuated antiproliferative potencies, while a similar structural modification of weakly potent p-acylaminophenols enhanced growth inhibitory potencies. However, conversion of the carboxylic acid moieties to their methyl esters completely abolished the cell growth inhibitory effects of both series. Insertion of a carboxylic acid moiety, which is important for binding to RA receptors, abolishes the action of p-alkylaminophenols, but enhances the action of p-acylaminophenols. This suggests that the amido functionality may be important for the growth inhibitory effects of the carboxylic acids.

Effects of Antibacterial Agents on Cancerous Cell Proliferation.

Myelosuppression, a side effect of anticancer drugs, makes people more susceptible to infectious diseases by compromising the immune system. When a cancer patient develops a contagious disease, treatment with an anticancer drug is suspended or postponed to treat the infectious disease. If there was a drug that suppresses the growth of cancer cells among antibacterial agents, it would be possible to treat both infectious diseases and cancer. Therefore, this study investigated the effect of antibacterial agents on cancer cell development. Vancomycin (VAN) had little effect on cell proliferation against the breast cancer cell, MCF-7, prostate cancer cell, PC-3, and gallbladder cancer cell, NOZ C-1. Alternatively, Teicoplanin (TEIC) and Daptomycin (DAP) promoted the growth of some cancer cells. In contrast, Linezolid (LZD) suppressed the proliferation of MCF-7, PC-3, and NOZ C-1 cells. Therefore, we found a drug that affects the growth of cancer cells among antibacterial agents. Next, when we examined the effects of the combined use of existing anticancer and antibacterial agents, we found VAN did not affect the growth suppression by anticancer agents. However, TEIC and DAP attenuated the growth suppression of anticancer agents. In contrast, LZD additively enhanced the growth suppression by Docetaxel in PC-3 cells. Furthermore, we showed that LZD inhibits cancer cell growth by mechanisms that involve phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt) pathway suppression. Therefore, LZD might simultaneously treat cancer and infectious diseases.

Inhibitory Effects of Vitamin A and Its Derivatives on Cancer Cell Growth Not Mediated by Retinoic Acid Receptors.

Vitamin A is an important trace essential nutrient. Vitamin A is present as a retinyl ester in animal foods and as ß-carotene (provitamin A), which is a precursor of vitamin A, in plant foods such as green and yellow vegetables. After ingestion and absorption in the body, these are converted into retinol and stored as retinyl esters in stellate cells in the liver. The stored retinyl esters are decomposed into retinol as needed, and converted into the aldehyde retinal, which plays an important role in vision. Retinoic acid (RA) has a variety of effects. In particular, RA is used as a therapeutic agent for acute promyelocytic leukemia. This review will cover (1) elucidation of anti-refractory cancer effects of retinol (vitamin A) not mediated by RA receptors, (2) elucidation of anti-cancer effects of RA not mediated by RA receptors and (3) the development of candidate new anti-cancer agents that combine the actions of RA and retinol. Lessons learned from these findings are that vitamin A has anti-cancer activity not mediated by RA receptors; that nutritional management of vitamin A leads to prevention and treatment of cancer, and that new compounds developed from RA derivatives represent good anti-cancer drug candidates that are in various stages of clinical trials.

A splicing factor phosphorylated by protein kinase A is increased in HL60 cells treated with retinoic acid.

Retinoic acid (RA) induces the differentiation of human promyelocytic leukemia HL60 cells into granulocytic cells and inhibits proliferation. Certain of actions of RA are mediated by RA nuclear receptors that regulate gene expression. However, it is also known that direct protein modification by RA (retinoylation) can occur. One such retinoylated protein in HL60 cells is a regulatory subunit of protein kinase A (PKA), which is increased in the nucleus following RA treatment and which then increases phosphorylation of other nuclear proteins. However, a complete understanding of which nuclear proteins are phosphorylated is lacking. In the current study, we employed mass spectrometry to identify one of the PKA-phosphorylated proteins as a serine/arginine-rich splicing factor 1 (SF2, SRSF1). We found that RA treatment increased the level of PKA-phosphorylated SF2 but decreased the level of SF2. While SF2 regulates myelogenous cell leukemia-1 (Mcl-1, anti-apoptotic factor), RA treatment reduced the level of Mcl-1L (full-length Mcl-1 long) and increased the level of Mcl-1S (Mcl-1 short; a short splicing variant of the Mcl-1). Furthermore, treatment with a PKA inhibitor reversed these effects on Mcl-1 and inhibited RA-induced cell differentiation. In contrast, treatment with a Mcl-1L inhibitor enhanced RA-induced cell differentiation. These results indicate that RA activates PKA in the nucleus, increases phosphorylation of SF2, raises levels of Mcl-1S and lowers levels of Mcl-1L, resulting in the induction of differentiation. RA-modified PKA may play an important role in inducing cell differentiation and suppressing cell proliferation.

Vitamin A in health care: Suppression of growth and induction of differentiation in cancer cells by vitamin A and its derivatives and their mechanisms of action.

Vitamin A is an important micro-essential nutrient, whose primary dietary source is retinyl esters. In addition, ß-carotene (pro-vitamin A) is a precursor of vitamin A contained in green and yellow vegetables that is converted to retinol in the body after ingestion. Retinol is oxidized to produce visual retinal, which is further oxidized to retinoic acid (RA), which is used as a therapeutic agent for patients with promyelocytic leukemia. Thus, the effects of retinal and RA are well known. In this paper, we will introduce (1) vitamin A circulation in the body, (2) the actions and mechanisms of retinal and RA, (3) retinoylation: another RA mechanism not depending on RA receptors, (4) the relationship between cancer and actions of retinol or ß-carotene, whose roles in vivo are still unknown, and (5) anti-cancer actions of vitamin A derivatives derived from fenretinide (4-HPR). We propose that vitamin A nutritional management is effective in the prevention of cancer.

Genome-wide association study of gastric cancer- and duodenal ulcer-derived Helicobacter pylori strains reveals discriminatory genetic variations and novel oncoprotein candidates.

Genome-wide association studies (GWASs) can reveal genetic variations associated with a phenotype in the absence of any hypothesis of candidate genes. The problem of false-positive sites linked with the responsible site might be bypassed in bacteria with a high homologous recombination rate, such as Helicobacter pylori, which causes gastric cancer. We conducted a small-sample GWAS (125 gastric cancer cases and 115 controls) followed by prediction of gastric cancer and control (duodenal ulcer) H. pylori strains. We identified 11 single nucleotide polymorphisms (eight amino acid changes) and three DNA motifs that, combined, allowed effective disease discrimination. They were often informative of the underlying molecular mechanisms, such as electric charge alteration at the ligand-binding pocket, alteration in subunit interaction, and mode-switching of DNA methylation. We also identified three novel virulence factors/oncoprotein candidates. These results provide both defined targets for further informatic and experimental analyses to gain insights into gastric cancer pathogenesis and a basis for identifying a set of biomarkers for distinguishing these H. pylori-related diseases.

Changes in the levels of α-actinin-4 in differentiating human myeloid leukemia cells induced by retinoic acid.

Retinoic acid (RA) induces granulocytic differentiation and inhibits the growth of human promyelocytic leukemia HL60 cells. α-Actinin-4 is a member of the α-actinin family, which exhibits unique mechanosensory regulation. Herein, we elucidated the effects of RA on α-actinin-4 expression during cell differentiation. RA increased the levels of α-actinin-4 protein significantly, while mRNA expression remained unchanged. In addition, RA treatment altered the intracellular localization of α-actinin-4 from the nucleus to the cytoplasm. Cells pretreated with RA, maintained α-actinin-4 protein levels after cycloheximide treatment as compared with control cells. The amount of ubiquitylated α-actinin-4 protein in RA-treated cells was less than in control cells. These results indicate that RA may inhibit nuclei transport and proteasomal degradation of α-actinin-4 protein. α-Actinin-4 may play a significant role in RA-induced differentiation, including the promotion of cytomorphology changes.

Risk Associated with Severe Hematological Toxicity in Patients with Urothelial Cancer Receiving Combination Chemotherapy of Gemcitabine and Cisplatin.

INTRODUCTION: Combination chemotherapy of gemcitabine and cisplatin (GC) is the standard treatment for patients with urothelial cancer (UC). However, hematological toxicity is a major side effect of GC therapy in patients with UC. In particular, discontinuation of the GC therapy is associated to adverse events such as hematological toxicity. Some studies have reported general risk factors of hematological toxicity such as age. However, little is known about risk factors for GC therapy-associated hematological toxicity in patients with UC. OBJECTIVE: We aimed to identify risk factors for hematological toxicity in patients with UC receiving GC therapy. METHODS: We performed a retrospective evaluation of the data of 128 patients with UC who received GC therapy. The study end point was defined as the occurrence of grade 4 neutropenia and grade ≥3 thrombocytopenia. Logistic regression analysis was used to determine risk factors that were significantly associated with neutropenia and thrombocytopenia. RESULTS: In total, 62 (48.4%) patients experienced grade 4 neutropenia, and 27 (21.1%) patients experienced grade ≥3 thrombocytopenia. In the multivariate analysis, performance status (PS) ≥1 (odds ratio [OR] 3.764, 95% confidence interval [CI] 1.410-10.047, p = 0.008) and neutrophil count (OR 0.648, 95% CI 0.468-0.898, p = 0.009) were significantly associated with grade 4 neutropenia. Platelet count (PLT) (OR 0.896, 95% CI 0.832-0.966, p = 0.004) and potassium (K) level (OR 6.966, 95% CI 1.313-36.989, p = 0.023) were also significantly associated with grade ≥3 thrombocytopenia. CONCLUSIONS: PS ≥ 1, neutrophil count, PLT, and K level were important risk factors for GC therapy-induced hematological toxicity in patients with UC. To continue GC therapy, further management systems by hematological toxicity risk factors for patients with UC will be required.

Increased Vancomycin Clearance in Patients with Solid Malignancies.

Vancomycin (VAN) is an anti-microbial agent used to treat a number of bacterial infections, which has a high incidence of nephrotoxicity. We examined the pharmacokinetics of VAN retrospectively based on trough concentrations at large scale and identified pharmacokinetic differences between Japanese patients having solid malignancy and non-malignancy patients. Data were analyzed from 162 solid malignancy patients and 261 non-malignancy patients, including the patient's background, VAN dose, and pharmacokinetics of VAN. We failed to detect differences in values for VAN clearance or shorter elimination half-lives between these two groups. In contrast, multiple regression analysis under adjusting for confounding factors by propensity score, showed that VAN clearance significantly increased in relation to solid malignancies in each stage. We conclude that VAN clearance in solid malignancy patients is increased and that the blood concentration of VAN becomes lower than expected. These results suggest that early monitoring of VAN levels in solid malignancy patients might be essential for maintaining desired effects without side-effects.

Early and midterm outcomes of celiac artery coverage during thoracic endovascular aortic repair.

BACKGROUND: In thoracic endovascular aortic repair (TEVAR), covering the celiac artery (CA) is sometimes necessary to secure the distal seal. We report the outcomes of planned CA coverage in our experience with TEVAR. METHODS: Cases requiring CA coverage during TEVAR from October 2008 to September 2018 were retrospectively reviewed. Patient demographics, indications for CA coverage, communication between the CA and the superior mesenteric artery (SMA), concomitant CA embolization, and perioperative and late results were collected in a prospective database and analyzed. RESULTS: During the study decade, 357 patients underwent TEVAR at our institution. Of these patients, 15 (4.2%) required CA coverage. All 15 patients were male, and the mean age was 72.8 years (range, 44-80 years). The mean aneurysm size was 67.5 mm (range, 50-82 mm). The etiologies included 10 degenerative aneurysms (66.7%; 2 ruptures [13.3%], 4 dissecting aneurysms [26.7%], and 1 case of type IB endoleak [6.7%]) after TEVAR. Communicating collaterals between the CA and the SMA were confirmed by preoperative computed tomography angiography in eight patients (53.3%) and by intraoperative angiography in four patients (26.7%). Seven patients (46.7%) underwent concomitant embolization of the CA. CA coverage offered a mean extension of 20.3 mm (range, 12-22 mm) in the length of the distal seal. Postoperative computed tomography angiography revealed a type IB endoleak that resolved spontaneously in one patient (6.7%). Postoperative complications included splenic infarction/pancreatitis in one patient (6.7%) and spinal cord ischemia in two patients (13.3%). There were no cases of postoperative in-hospital mortality. During the follow-up period (mean, 3.6 years; range, 0.9-8.0 years), two patients developed a new type IB endoleak. One patient underwent distal extension of the stent graft with ilio-SMA bypass, and one patient was observed conservatively in accordance with the patient's decision. There were no cases of type II endoleak via the CA. Most aneurysms (86.7%) were stable or reduced in size at the most recent follow-up. There were no cases of targeted aneurysm-related death during the follow-up period. CONCLUSIONS: Our study demonstrates the safety and efficacy of CA coverage in facilitating adequate distal sealing in selected patients undergoing TEVAR. Because the distal sealing length is not completely sufficient in most cases requiring CA coverage, the long-term efficacy of CA coverage during TEVAR should be determined in a large prospective study.

Suprarenal fixation is associated with worse midterm renal function after endovascular abdominal aortic aneurysm repair compared with infrarenal fixation.

BACKGROUND: Several reports have indicated that suprarenal (SR) fixation may impair renal function after endovascular abdominal aortic aneurysm repair (EVAR). However, most were short-term or at most, 1-year observational studies; therefore, the midterm effects on renal function remain unclear. This study aimed to identify predictors of midterm renal dysfunction after EVAR and compare renal outcomes in patients after EVAR with SR and infrarenal (IR) fixation. METHODS: A total of 467 patients who underwent EVAR of nonruptured IR abdominal aortic aneurysm between 2007 and 2014 were reviewed in a prospectively collected database. Patients on hemodialysis at baseline were excluded. Among the remaining patients, those with 3-year laboratory testing were included in this study. Patients who developed acute kidney injury were excluded from the late renal function estimation. Predictors of 3-year renal function decline were estimated using logistic regression analysis. In addition, patients undergoing EVAR with IR (IR group) and SR fixation devices (SR group) were propensity matched by age, sex, baseline renal function, baseline aneurysm diameter, comorbidities, smoking habits, and regular use of medicines that may act on kidney function. Changes in renal function after surgery were compared between the IR group and the SR group. RESULTS: During the study period, 237 patients (102 IRs and 135 SRs) were followed up with laboratory testing 3 years after surgery. Logistic regression analysis revealed that the use of a SR fixation device was independently predictive of a more than 20% decrease in the estimated glomerular filtration rate at 3 years after EVAR (odds ratio, 2.06; 95% confidence interval, 1.18-3.58; P = .011). Eleven patients who developed acute kidney injury (1 IR and 10 SRs) were excluded from the subsequent analysis. After propensity score matching, 87 pairs were selected (mean age, 77.2 ± 6.3 years; 151 males [86.8%]). The mean follow-up duration was 5.5 ± 1.8 years. In the SR group, estimated glomerular filtration rate at 3 years after surgery decreased significantly more than that in the IR group (mean of 17.8% vs 11.6%, respectively; P = .034). CONCLUSIONS: This study suggests that, compared with EVAR with IR endograft fixation, EVAR with SR endograft fixation is associated with worse outcomes for midterm renal function.

Augmented Renal Clearance of Vancomycin in Hematologic Malignancy Patients.

The pharmacokinetics of vancomycin (VAN) was retrospectively examined based on trough concentrations at large scale to identify pharmacokinetic differences between Japanese hematologic malignancy and non-malignancy patients. Data from 261 hematologic malignancy patients and 261 non-malignancy patients, including the patient's background, VAN dose, and pharmacokinetics of VAN estimated by an empirical Bayesian method, were collected and analyzed. Our results showed significantly higher values for VAN clearance and shorter elimination half-lives in patients with hematologic malignancies than non-malignancy patients. In addition, multiple regression analysis under adjusting for confounding factors by propensity score, showed that VAN clearance significantly increased in relation to hematologic malignancies. In conclusion, since in hematologic cancer patients VAN clearance is increased, the blood concentration of VAN becomes lower than expected and this may contribute to the survival of resistant bacteria when VAN is administered at low doses. These results suggest that early monitoring of VAN levels in hematologic cancer patients might be recommended to maintain desired effects without side-effects.

Effect of Intraoperative Division of the Left Renal Vein on the Fate of Renal Function and Left Renal Volume After Open Repair of Para- and Juxtarenal Aortic Aneurysm.

BACKGROUND: The effect of left renal vein division (LRVD) during open surgery (OS) for pararenal and juxtarenal abdominal aortic aneurysm (P/JRAA) on postoperative renal function remains controversial, so we focused on chronic renal decline (CRD) and separately examined renal volume as a surrogate index of split renal function.Methods and Results:The 115 patients with P/JRAA treated with OS from June 2007 to January 2017 were reviewed: 26 patients without LRVD were matched to 27 patients with LRVD according to preoperative chronic kidney disease (CKD) stage and proximal clamp sites. The effect of LRVD on CRD was investigated by a time-to-event analysis. During a median follow-up of 23.5 months, CRD occurred in 5 patients with LRVD and in 4 patients without LRVD. Comparison of freedom from CRD showed no significant difference between the matched groups (P=0.870). The separate renal volumes were evaluated before surgery and at 1 and 2 years of follow-up using CT images from 18 patients with LRVD. At 2 years, the mean renal volume had decreased by 15% in the left kidney and by 9% in the right kidney (P=0.052 and 0.148, respectively), but the left-to-right renal volume ratio showed no significant change (P=0.647). CONCLUSIONS: LRVD had no significant effect on CRD or left renal volume relative to the right renal volume for up to 2 years.

Growth Inhibition of Human Breast and Prostate Cancer Cells by Cinnamic Acid Derivatives and Their Mechanism of Action.

Cancer is the leading cause of death and there is a particularly pressing need to develop effective treatments for breast and prostate cancer. In the current study, we show the inhibitory effects of cinnamic acid derivatives, including caffeic acid phenethyl ester (CAPE, 1), on the growth of breast and prostate cancer cells. Among the compounds examined, 3,4,5-trihydroxycinnamic acid decyl ester (6) showed the most potent inhibition of cancer cell growth by the induction of apoptosis. Compound 6 could be a new anti-cancer agent for use against breast and prostate cancer.

Associations of nutritional status and muscle size with mortality after open aortic aneurysm repair.

OBJECTIVE: Open surgical repair (OSR) for abdominal aortic aneurysms is a more invasive approach than endovascular aneurysm repair but has more enduring results and may lead to a lower reintervention rate. Therefore, strict selection of patients should be based on assessments of both early and late outcomes. The controlling nutritional status (CONUT) score and skeletal muscle mass index (SMI) have been reported as indicators of nutritional status and muscle size, respectively. The aim of this study was to identify prognostic factors, including sarcopenia and nutritional status, for early and late outcomes. METHODS: We reviewed data from 360 consecutive abdominal aortic aneurysm patients who underwent OSR from 2007 to 2014. We collected data on patients' characteristics, nutritional status (CONUT score), and muscle size (SMI). Cox proportional hazards analysis and logistic regression analysis identified independent predictors of midterm mortality and Clavien-Dindo class IV complications as late and early outcomes, respectively. RESULTS: During the study period, 360 patients underwent elective OSR. The following characteristics were associated with midterm mortality: age >71 years (hazard ratio [HR], 4.92; 95% confidence interval [CI], 1.41-17.13; P = .01), low SMI (HR, 4.32; 95% CI, 1.16-16.13; P = .03), CONUT score indicating a moderate risk of malnutrition (vs normal status or mild risk: HR, 4.16; 95% CI, 1.03-16.76; P = .045), and estimated glomerular filtration rate <30 mL/min/1.73 m2 (HR, 3.54; 95% CI, 1.09-11.47; P = .035). Two patients died within 30 days of undergoing OSR (0.6%). A CONUT score indicating moderate risk (HR, 4.42; 95% CI, 1.01-19.28; P = .048), estimated glomerular filtration rate <30 mL/min/1.73 m2 (HR, 7.34; 95% CI, 2.20-24.51; P < .001), and diabetes mellitus (HR, 3.71; 95% CI, 1.25-11.00; P = .02) were independent predictors of Clavien-Dindo class IV complications. CONCLUSIONS: These results may be useful for identifying and optimizing treatment of high-risk patients who will not benefit from OSR so that endovascular aneurysm repair or no intervention can be recommended. Consideration of nutritional status and sarcopenia may therefore support the development of a more personalized, cost-effective treatment strategy.

[Analysis of the Risk Factors Associated with Minor Bleeding in Patients with Venous Thromboembolism during Treatment with Direct Oral Anticoagulants].

Direct oral anticoagulants (DOACs) are safe and efficacious when compared to warfarin for patients with venous thromboembolism (VTE). However, bleeding is a major side effect of anticoagulant therapy in VTE patients. Discontinuation of the DOACs associated to adverse events such as bleeding. The HAS-BLED score predicts warfarin-associated hemorrhage. However, little is known about risk factors for DOAC-associated minor bleeding in VTE patients. We aimed to identify risk factors for minor bleeding in VTE patients that were treated with edoxaban, rivaroxaban, or apixaban. We retrospectively evaluated the data of 212 VTE patients who received treatment with a DOAC. The study endpoint was defined as the occurrence of minor bleeding. Logistic regression analysis was used to determine risk factors that were significantly associated with minor bleeding. A total of 36 (17.0%) patients experienced minor bleeding, with rates of 15.7%, 0%, and 21.3% for edoxaban, rivaroxaban, and apixaban, respectively. In the multivariate analysis, bleeding history or predisposition [odds ratio (OR) 6.083, 95% confidence interval (CI) 2.131-17.364, p=0.001] and cancer (OR 6.397, 95% CI 2.858-14.317, p<0.001) were significantly associated with minor bleeding. Bleeding history or predisposition and cancer were the most important risk factors for DOAC-induced minor bleeding in VTE patients in this study. To continue anticoagulant therapy of the DOACs, further management systems by minor bleeding risk factors for patients with VTE will be required.

Proximal Bare Stent May Reduce Bird-Beak Configuration, Which is Associated with Distal Migration of Stent Graft in the Aortic Arch.

BACKGROUND: Prior studies have shown that a bird-beak configuration causes serious complications after thoracic endovascular aortic repair (TEVAR). However, factors that cause bird-beak configurations are poorly understood. The purpose of this study was to assess the influences of anatomical and device-related factors on bird-beak configuration. METHODS: Sixty-eight consecutive patients (47 men, mean age, 72.8 ± 9.8 years) who underwent TEVAR with proximal fixation in zones 1 to 3 from March 2009 to February 2017 were included. Preoperative and postoperative computed tomography (CT) scans were retrospectively reviewed. Relationships between the incidence of a bird-beak configuration, preoperative aortic arch morphology, and type of stent graft were estimated. The influence of a bird-beak configuration on endograft migration over time was also estimated for 47 patients who underwent CT 12 months after TEVAR. RESULTS: The patients' aortic arch pathologies included 52 aneurysms, 11 aortic dissections, 4 pseudoaneurysms, and 1 patent ductus arteriosus. Stent grafts with (the proximal bare stent group [PBS group]) and without (the nonbare stent group [NBS group]) a proximal bare stent were implanted in 24 and 44 patients, respectively. A bird-beak configuration was detected in 30 patients (mean length ± standard deviation [SD], 6.2 ± 3.4 mm; mean angle ± SD, 31.7 ± 14.7°) and was significantly more frequent in the NBS group (n = 29) than in the PBS group (n = 1) (P < 0.001). Proximal landing zone, aortic lengths, and aortic arch morphology, including the radius, tortuosity, and angulation of aortic arch curvature, were not associated with the bird-beak configuration. The migration distance after 1 year was significantly longer in patients with a bird-beak configuration (3.5 ± 6.1 mm) than in patients without a bird-beak configuration (0.5 ± 1.0 mm) (P = 0.015). CONCLUSION: This study demonstrated that in aortic arch TEVAR, the use of stent graft with a proximal bare stent may reduce bird-beak configuration, which is associated with distal migration of the stent graft during follow-up.