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Diffusion-weighted magnetic resonance imaging (DW-MRI) performed before target temperature management, within 6 h of return of spontaneous circulation (ROSC), is defined as ultra-early DW-MRI. In previous studies, high-signal intensity (HSI) on ultra-early DW-MRI can predict poor neurological outcomes (Cerebral Performance Category 3-5 at 6-months post-ROSC). We aimed to assess the optimal-timing for ultra-early DW-MRI to avoid false-negative outcomes post out-of-hospital cardiac arrest, considering cardiopulmonary resuscitation (CPR) factors. The primary outcomes were HSI in the cerebral cortex or deep gray matter on ultra-early DW-MRI. The impact of CPR factors and ROSC to DW-MRI scan-interval on HSI-presence was assessed. Of 206 included patients, 108 exhibited HSI-presence, exclusively associated with poor neurological outcomes. In multivariate regression analysis, ROSC to DW-MRI scan-interval (adjusted odds ratio [aOR], 1.509; 95% confidence interval (CI): 1.113-2.046; P = 0.008), low-flow time (aOR, 1.176; 95%CI: 1.121-1.233; P < 0.001), and non-shockable rhythm (aOR, 9.974; 95%CI: 3.363-29.578; P < 0.001) were independently associated with HSI-presence. ROSC to DW-MRI scan-interval cutoff of ≥ 2.2 h was particularly significant in low-flow time ≤ 21 min or shockable rhythm group. In conclusion, short low-flow time and shockable rhythm require a longer ROSC to DW-MRI scan-interval. Prolonged low-flow time and non-shockable rhythm reduce the need to consider scan-interval., (© 2024. The Author(s).)

Background This study aimed to determine the proportion of organ donors suitable for donation after circulatory death and investigate the current process followed by critical care physicians for declaring circulatory death to establish organ donation. Methods This observational study involved potential organ donors who had recently died after discontinuation of life support. We conducted an online survey of intensivists to determine how these deaths were confirmed. Results Among the 177 patients who died after withdrawal of life-sustaining treatment across 19 intensive care units in 11 institutions, 49 (27.7%) were considered potential donors. According to general medical criteria for organ donation, 20 (11.3%) patients were identified as medically suitable donors. Notably, 116 (73.9%) patients exhibited a flat electrocardiogram within 5 min after the loss of pulse. In the survey, 90 physicians (59.2%) agreed to implement the concept of the 5-min no-touch period for the declaration of circulatory death. Conclusions This study found that 11.3% of the patients who died following the withdrawal of life-sustaining treatment in the intensive care units were identified as suitable donors after circulatory death. Most of critical care physicians agree with the concept of a 5-min no-touch period for the declaration of circulatory death., (© 2024. The Author(s).)

We evaluated alterations in cerebrospinal fluid (CSF) flow based on the neurological prognosis of out-of-hospital cardiac arrest (OHCA) patients. This prospective observational study was conducted from May 2023 to June 2024. Stroke distance was measured using magnetic resonance imaging flowmetry immediately and at 72 h after return of spontaneous circulation (ROSC), with negative values indicating caudocranial direction. The caudocranial direction of CSF flow was observed in 17 (56.7%) patients immediately after ROSC, and in 20 (66.7%) patients at 72 h after ROSC. There was no significant difference in the occurrence of caudocranial CSF flow immediately after ROSC between the groups with good and poor neurological prognosis [6 (50.0%) vs. 11 (61.1%); p = 0.55]. However, the occurrence of caudocranial CSF flow at 72 h after ROSC was significantly higher in the group with poor neurological prognosis compared to the group with good neurological prognosis [3 (25.0%) vs. 17 (94.4%); p < 0.001]. This study demonstrated that the occurrence of caudocranial CSF flow at 72 h after ROSC was significantly higher in the group with poor neurological prognosis compared to the group with good neurological prognosis., (© 2024. The Author(s).)

The optimal anesthetic agent for radiofrequency catheter ablation (RFCA) of atrial fibrillation (AF) and its impact on the recovery profiles remain uncertain. We compared the recovery and hemodynamic parameters between the remimazolam-flumazenil and propofol groups during RFCA. Patients were randomized into the remimazolam-flumazenil and propofol groups. The primary outcome measure was the time to eye opening following the discontinuation of anesthetic agents. Secondary outcomes included time to extubation, time to discharge from the operating room, intraprocedural hemodynamic variables and postoperative quality outcomes. Fifty-three patients were included in the final analysis (n = 26 in the remimazolam-flumazenil and n = 27 in the propofol group). The time to eye opening was significantly shorter in the remimazolam-flumazenil group compared to the propofol group (median [interquartile range]: 174 [157-216] vs. 353 [230-483] s, P < 0.001). The mean blood pressure and bispectral index were significantly higher in the remimazolam-flumazenil group compared to the propofol group (mean difference [95% CI], 7.2 [1.7-12.7] mmHg and 6 [3-8]; P = 0.011 and < 0.001, respectively), which were within target ranges in both groups. Other secondary outcomes were comparable between the groups. Consequently, remimazolam emerges as a promising anesthetic agent, characterized by rapid recovery and stable hemodynamics, during RFCA of AF.Trial registration: NCT05397886., (© 2024. The Author(s).)

We investigated three-dimensional (3D) eyeball protrusion and its association with the offset between the lamina cribrosa (LC) and Bruch's membrane opening (BMO). 3D-MRI scans were taken from 93 subjects (186 eyes). An ellipsoid was fitted along the posterior 2/3 contour of each eyeball. Eyeball asymmetry with focal bulging was determined by the existence of an adjacent outward protrusion/reciprocal inward depression pair, and the angular deviation of the outermost protruded point (OPP) was measured from the nasal side of the fovea-BMO axis. The LC/BMO offset was evaluated by measuring the central retinal vascular trunk (CRVT) location from the BMO center: (1) the angular deviation and (2) the offset index as the ratio between the CRVT-BMO center distance and the BMO radius in the same direction. Seventy-nine eyes (42%) were classified as having eyeball asymmetry, which had a more superior LC/BMO offset (P < 0.001) and a larger offset index (P = 0.002). In those eyes, the angular deviation of the OPP showed a significant correlation with that of the LC/BMO offset (r = -0.724, P < 0.001), as did protrusion depth with the offset index (r = 0.291, P = 0.009). The presence of eyeball asymmetry was associated with superior LC/BMO offset (P = 0.004) and larger offset index (P = 0.009). Superior LC/BMO offset was associated with older age (P < 0.001), shorter axial length (P < 0.001) and inferior location of OPP (P < 0.001). The location and extent of focal bulging were closely associated with those of LC/BMO offset. This indicates that focal bulging during expansion might be associated with diverse directionality of LC/BMO offset., (© 2024. The Author(s).)

We investigated the agreement between the jugular bulb (JB) and cerebrospinal fluid (CSF) lactate levels. The study was conducted from July 2021 to June 2023 as a prospective observational cohort study at a single center. The right jugular vein was accessed, and the placement of JB catheter tip was confirmed using lateral cervical spine X-ray. A lumbar catheter was inserted between the 3rd and 4th lumbar spine of the patient. Lactate levels were measured immediately, 24 h, 48 h, and 72 h after ROSC. In patients with a good neurological prognosis, kappa between JB and CSF lactate levels measured immediately, at 24 h, 48 h, and 72 h after ROSC were 0.08, 0.36, 0.14, - 0.05 (p = 0.65, 0.06, 0.48, and 0.75, respectively). However, in patients with a poor neurological prognosis, kappa between JB and CSF lactate levels measured immediately, at 24 h, 48 h, and 72 h after ROSC were 0.38, 0.21, 0.22, 0.12 (p = 0.001, 0.04, 0.04, and 0.27, respectively). This study demonstrated that JB lactate levels exhibited significant agreement with arterial lactate levels, compared to CSF lactate levels. Therefore, this should be considered when using JB lactate to monitor cerebral metabolism., (© 2024. The Author(s).)

Sex differences in the in-hospital management of sepsis exist. Previous studies either included patients with sepsis that was defined using previous definitions of sepsis or evaluated the 3-h bundle therapy. Therefore, this study sought to assess sex differences in 1-h bundle therapy and in-hospital management among patients with sepsis and septic shock, defined according to the Sepsis-3 definitions. This observational study used data from Korean Shock Society (KoSS) registry, a prospective multicenter sepsis registry. Adult patients with sepsis between June 2018 and December 2021 were included in this study. The primary outcome was adherence to 1-h bundle therapy. Propensity score matching (PSM) and multivariable logistic regression analyses were performed. Among 3264 patients with sepsis, 3129 were analyzed. PSM yielded 2380 matched patients (1190 men and 1190 women). After PSM, 1-h bundle therapy was performed less frequently in women than in men (13.0% vs. 19.2%; p < 0.001). Among the bundle therapy components, broad-spectrum antibiotics were administered less frequently in women than in men (25.4% vs. 31.6%, p < 0.001), whereas adequate fluid resuscitation was performed more frequently in women than in men (96.8% vs. 95.0%, p = 0.029). In multivariable logistic regression analysis, 1-h bundle therapy was performed less frequently in women than in men [adjusted odds ratio (aOR) 1.559; 95% confidence interval (CI) 1.245-1.951; p < 0.001] after adjustment. Among the bundle therapy components, broad-spectrum antibiotics were administered less frequently to women than men (aOR 1.339, 95% CI 1.118-1.605; p = 0.002), whereas adequate fluid resuscitation was performed more frequently for women than for men (aOR 0.629, 95% CI 0.413-0.959; p = 0.031). Invasive arterial blood pressure monitoring was performed less frequently in women than in men. Resuscitation fluid, vasopressor, steroid, central-line insertion, ICU admission, length of stay in the emergency department, mechanical ventilator use, and renal replacement therapy use were comparable for both the sexes. Among patients with sepsis and septic shock, 1-h bundle therapy was performed less frequently in women than in men. Continuous efforts are required to increase adherence to the 1-h bundle therapy and to decrease sex differences in the in-hospital management of patients with sepsis and septic shock., (© 2024. The Author(s).)

Administration of sedatives for post-resuscitation care can complicate the determination of the optimal timing to avoid inappropriate, pessimistic prognostications. This prospective study aimed to investigate the distribution and elimination kinetics of midazolam (MDZ) and its metabolites, and their association with awakening time. The concentrations of MDZ and its seven metabolites were measured immediately and at 4, 8, 12, and 24 h after the discontinuation of MDZ infusion, using liquid chromatography-tandem mass spectrometry. The area under the time-plasma concentration curve from 0 to 24 h after MDZ discontinuation (AUC last ) was calculated based on the trapezoidal rule. Of the 15 enrolled patients, seven awakened after the discontinuation of MDZ infusion. MDZ and three of its metabolites were major compounds and their elimination kinetics followed a first-order elimination profile. In the multivariable analysis, only MDZ was associated with awakening time (AUC last : R 2  = 0.59, p = 0.03; AUC inf : R 2  = 0.96, p < 0.001). Specifically, a 0.001% increase in MDZ AUC was associated with a 1% increase in awakening time. In the individual regression analysis between MDZ concentration and awakening time, the mean MDZ concentration at awakening time was 16.8 ng/mL. The AUC of MDZ is the only significant factor associated with the awakening time., (© 2024. The Author(s).)

This study investigated the prognostic performance of combination strategies using a multimodal approach in patients treated after cardiac arrest. Prospectively collected registry data were used for this retrospective analysis. Poor outcome was defined as a cerebral performance category of 3-5 at 6 months. Predictors of poor outcome were absence of ocular reflexes (PR/CR) without confounding factors, a highly malignant pattern on the most recent electroencephalography, defined as suppressed background with or without periodic discharges and burst-suppression, high neuron-specific enolase (NSE) after 48 h, and diffuse injury on imaging studies (computed tomography or diffusion-weighted imaging [DWI]) at 72-96 h. The prognostic performances for poor outcomes were analyzed for sensitivity and specificity. A total of 130 patients were included in the analysis. Of these, 68 (52.3%) patients had poor outcomes. The best prognostic performance was observed with the combination of absent PR/CR, high NSE, and diffuse injury on DWI [91.2%, 95% confidence interval (CI) 80.7-97.1], whereas the combination strategy of all available predictors did not improve prognostic performance (87.8%, 95% CI 73.8-95.9). Combining three of the predictors may improve prognostic performance and be more efficient than adding all tests indiscriminately, given limited medical resources., (© 2023. The Author(s).)

Sugammadex reverses neuromuscular blockade by encapsulating steroidal neuromuscular blockers; therefore, it does not pharmacologically affect sedation levels. However, some clinicians avoid using it because of sudden unwanted acting out or patient arousal. Previous studies suggested sugammadex-induced awakening, but frontal muscle contraction after sugammadex administration compromised reliability of results obtained from EEG-based anesthesia depth monitoring tools like bispectral index (BIS). We hypothesized that sugammadex would affect patients' arousal depending on their baseline levels of sedation. We evaluated arousal signs after sugammadex administration with BIS between 25 - 35 and 45 - 55 under steady-state propofol-remifentanil anesthesia at the end of a surgery (n = 33 in each group). After sugammadex administration, twelve patients with a BIS of 45 - 55 showed clinical signs of awakening but none with a BIS of 25 - 35 (36.4% vs. 0%, P = 0.001). The distribution of the modified observer's assessment of alertness/sedation scale scores was also significantly different between the two groups (P < 0.001). Changes in the BIS were significantly greater in the BIS 45 - 55 than in the 25 - 35 group (median difference, 7; 95% CI 2 - 19, P = 0.002). Arousal after sugammadex was affected by patient sedation levels, and clinical signs of awakening appeared only in those with BIS 45 - 55. Unwanted arousal of the patient should be considered when using sugammadex under shallow anesthesia.Clinical trial registry number: Clinical Trial Registry of Korea ( https://cris.nih.go.kr ; Principal investigator: Jieae Kim; Registration number: KCT0006248; Date of first registration: 11/06/2021)., (© 2023. The Author(s).)

Catheter-based approaches may have inherent limitations in achieving effective renal denervation (RDN) and treatment of atrial fibrillation (AF). This study aimed to investigate the acute effects of novel laparoscopic RDN on modulating AF inducibility using a swine model. Four and five swine were randomly allocated to the sham and RDN groups, respectively. Each swine underwent measurement of the atrial effective refractory period (AERP) and AF induction tests using burst atrial pacing before and immediately after sham or RDN procedures with and without vagal nerve stimulation (VNS). A laparoscopic RDN procedure circumferentially ablated the renal nerves round the renal arteries using radiofrequency energy. There was no significant difference in the baseline AERP between the two groups (p > 0.05). Under VNS, AERP was significantly increased by 20 ms after laparoscopic RDN (95% CI = 0-30, p = 0.004). Compared to the sham group, the RDN group showed significantly reduced AF inducibility [OR (95% CI) = 0.32 (0.13-0.76) and 0.24 (0.11-0.57) with and without VNS, respectively]. After laparoscopic RDN, the duration of inducible AF episodes was significantly shortened from 28 (10-77) s to 7 (3-11) s (p < 0.001). The novel laparoscopic RDN can immediately reduce AF inducibility in a swine model., (© 2023. The Author(s).)

We compared the cut-off and prognostic value of serum neuron-specific enolase (NSE) between groups with and without severe blood-brain barrier (BBB) disruption to reveal that a cause of various serum NSE cut-off value for neurological prognosis is severe BBB disruption in out-of-hospital cardiac arrest (OHCA) patients underwent target temperature management (TTM). This was a prospective, single-centre study conducted from January 2019 to June 2021. Severe BBB disruption was indicated using cerebrospinal fluid-serum albumin quotient values > 0.02. The area under the receiver operating characteristic curve of serum NSE obtained on day 3 of hospitalisation to predict poor outcomes was used. In patients with poor neurologic outcomes, serum NSE in those with severe BBB disruption was higher than in those without (P = 0.006). A serum NSE cut-off value of 40.4 μg/L for poor outcomes in patients without severe BBB disruption had a sensitivity of 41.7% and a specificity of 96.0%, whereas a cut-off value of 34.6 μg/L in those with severe BBB disruption had a sensitivity of 86.4% and a specificity of 100.0%. We demonstrated that the cut-off and prognostic value of serum NSE were heterogeneous, depending on severe BBB disruption in OHCA patients treated with TTM., (© 2022. The Author(s).)

We investigated whether pulmonary function tests (PFTs) can predict pulmonary complications and if they are, to find new cutoff values in current open lung resection surgery. In this observational study, patients underwent open lung resection surgery at a tertiary hospital were analyzed (n = 1544). Various PFTs were tested by area under the receiver-operating characteristic curve (AUC ROC ) to predict pulmonary complications until 30 days postoperatively. In results, PFTs were generally not effective to predict pulmonary complications (AUC ROC : 0.58-0.66). Therefore, we could not determine new cutoff values, and used previously reported cutoffs for post-hoc analysis [predicted postoperative forced expiratory volume in one second (ppoFEV 1 ) < 40%, predicted postoperative diffusing capacity for carbon monoxide (ppoDL CO ) < 40%]. In multivariable analysis, old age, male sex, current smoker, intraoperative transfusion and use of inotropes were independent risk factors for pulmonary complications (model 1: AUC ROC 0.737). Addition of ppoFEV 1 or ppoDL CO  < 40% to model 1 did not significantly increase predictive capability (model 2: AUC ROC 0.751, P = 0.065). In propensity score-matched subgroups, patients with ppoFEV 1 or ppoDL CO  < 40% showed higher rates of pulmonary complications [13% (21/160) vs. 24% (38/160), P = 0.014], but no difference in in-hospital mortality [3% (8/241) vs. 6% (14/241), P = 0.210] or mean survival duration [61 (95% CI 57-66) vs. 65 (95% CI 60-70) months, P = 0.830] compared to patients with both > 40%. In conclusion, PFTs themselves were not effective predictors of pulmonary complications. Decision to proceed with surgical resection of lung cancer should be made on an individual basis considering other risk factors and the patient's goals., (© 2022. The Author(s).)

Atopic dermatitis (AD) is associated with allergic comorbidities, such as asthma, allergic rhinitis (AR), and allergic contact dermatitis (ACD). The etiology of keloid is largely unknown; however, AD and keloid share inflammatory pathways characterized by T-helper cell 2 cytokines and increased dermal fibroblast activity. The prevalence of keloids has been reported to increase in patients with AD, but it remains controversial. This study aimed to estimate the prevalence of keloids in patients with AD, and compare it with the prevalence of other comorbidities of AD. We assessed the Korean National Health Information Database and medical records including coexisting asthma, AR, and ACD. Single and multiple logistic regression models were created for keloids and each allergic disease. The prevalence of keloids was higher in the AD group than in the control group. Among patients with AD, adolescents and adults had a higher prevalence of keloids than infants and children. The risk of keloids was high with AD alone, and coexisting asthma significantly increased the risk. Similarly, the risk of keloids was higher in AR associated with AD and ACD associated with AD than in AD alone. Thus, among Koreans, patients with AD have a higher risk of keloid development, with coexisting allergic diseases increasing the risk., (© 2021. The Author(s).)

We compared the central retinal vascular trunk (CRVT) position, as a surrogate of lamina cribrosa (LC) offset, with the anterior scleral opening (ASCO) offset from the Bruch's membrane opening (BMO). Based on the BMO-centered radial scans, the BMO and ASCO margins were demarcated, and each center was determined as the center of the best-fitted ellipse for each margin. The ASCO/BMO offset was defined as the offset between each center. Angular deviations and the extent of ASCO and CRVT offsets from the BMO center were compared directly. Incomplete demarcation of ASCO was found in 20%, which was associated with a larger BMO area and a larger ASCO offset from the BMO. The angular deviation of ASCO offset was associated with that of CRVT offset and that of the longest externally oblique border. The ASCO offset was smaller than the CRVT offset, and, unlike the CRVT offset, it was rarely deviated to the inferior side. The complete ASCO margin might not be demarcatable when determined on BMO-centered radial scans in the presence of an offset. Also, the ASCO, which reflects only the superficial scleral layer, might not reflect the LC position, because the LC might be shifted further from the ASCO., (© 2021. The Author(s).)

Findings obtained on objective assessments to evaluate sensitive skin do not correlate well with the symptomatology. We utilized reflectance confocal microscopy (RCM) to compare transepidermal application of zinc in sensitive and non-sensitive skin. Thirty-six subjects participated in this study. They were divided into groups based on lactic acid sting test (LAST):'stinger' and 'non-stinger'; transepidermal water loss (TEWL) measurements; and sensitivity self-assessments: 'sensitive' and 'non-sensitive'. RCM images were taken to visualize transepidermal application of topically-applied zinc. The intensity of zinc reflectance at different depths was measured by ImageJ software. Based on LAST scores, the 'stinger' group showed significantly higher reflectance of zinc at 8 µm (stratum corneum) [face (P < 0.001), forearm (P = 0.004)], and at 80-104 µm (dermo-epidermal junction layer) on the face. High-TEWL group showed increased zinc reflectance at 8-24 µm (tight junction layer, P < 0.001). There were no significant differences amongst subjects self-reporting 'sensitive' and 'non-sensitive' skin. RCM demonstrates that in sensitive skin, there is deeper and higher reflectance of zinc at multiple depths. Structural differences are also visualized. We suggest that RCM is a useful tool for evaluating skin barrier integrity.

We aimed to investigate the association between the combination of unhealthy lifestyle and risk of AF. Subjects aged 66 years who underwent health examination from 2009 to 2015 were included. The cohort was divided into 8 groups by the combination of unhealthy lifestyle including current smoking, heavy drinking (> 30 g/day), and lack of regular exercise, and followed up for new-onset AF till December 31, 2017. Among 1,719,401 subjects, 47,334 had incident AF (5.5 per 1000 person-years) during a 5-year mean follow-up period. Lack of regular exercise was the most powerful factor to be associated with a higher risk of AF as a single factor (adjusted hazard ratio 1.11, 95% confidence interval 1.08-1.13). Amongst combinations of two unhealthy lifestyle factors, current smoking with heavy drinking, lack of regular exercise with heavy drinking, and lack of regular exercise with current smoking were associated with a 6%, 15%, and 20% higher risks of AF, respectively. A cluster of three unhealthy lifestyle components was associated with a 22% higher risk of AF. Increased numbers of unhealthy lifestyle factors were associated with a higher risk of incident AF. These findings support the promotion of a healthy lifestyle to lower the risk of new-onset AF.

Restrictive fluid management has been recommended for thoracic surgery. However, specific guidelines are lacking, and there is always concern regarding impairment of renal perfusion with a restrictive policy. The objective of this study was to find the net intraoperative fluid infusion rate which shows the lowest incidence of composite complications (either pulmonary complications or acute kidney injury) in open thoracotomy. We hypothesized that a certain range of infusion rate would decrease the composite complications within postoperative 30 days. All patients (n = 1,031) who underwent open thoracotomy at a tertiary care university hospital were included in this retrospective study. The time frame of fluid monitoring was from the start of operation to postoperative 24 hours. The cutoff value of the intraoperative net fluid amount was 4-5 ml.kg -1 .h -1 according to the minimum p-value method, thus, patients were divided into Low (≤3 ml.kg -1 .h -1 ), Cutoff (4-5 ml.kg -1 .h -1 ) and High (≥6 ml.kg -1 .h -1 ) groups. The Cutoff group showed the lowest composite complication rate (19%, 12%, and 13% in the Low, Cutoff, and High groups, respectively, P = 0.0283; Low vs. Cutoff, P = 0.0324, Bonferroni correction). Acute respiratory distress syndrome occurred least frequently in the Cutoff group (7%, 3%, and 6% for the Low, Cutoff, and High groups, respectively, P = 0.0467; Low vs. Cutoff, P = 0.0432, Bonferroni correction). In multivariable analysis, intraoperative net fluid infusion rate was associated with composite complications, and the Cutoff group decreased risk (odds ratio 0.54, 95% confidence interval: 0.35-0.81, P = 0.0035). In conclusion, maintaining intraoperative net fluid infusion at 4-5 ml.kg -1 .h -1 was associated with better results in open thoracotomy, in terms of composite complications, compared to more restrictive fluid management.

Axitinib, small molecule tyrosine kinase inhibitor, demonstrates anti-cancer activity for various solid tumors. We investigated anti-cancer effect of axitinib in epithelial ovarian cancer (EOC). We treated EOC cells (A2780, HeyA8, RMG1, and HeyA8-MDR) with axitinib to evaluate its effects on cell viabilty, apoptosis and migration. Western blots were performed to assess VEGFR2, ERK, and AKT levels, and ELISA and FACS to evaluate apoptosis according to axitinib treatment. In addition, in vivo experiments in xenografts using A2780, RMG1, and HeyA8-MDR cell lines were performed. We repeated the experiment with patient-derived xenograft models (PDX) of EOC. Axitinib significantly inhibited cell survival and migration, and increased apoptosis in EOC cells. The expression of VEGFR2 and phosphorylation of AKT and ERK in A2780, RMG1, and HeyA8 were decreased with axitinib treatment in dose-dependent manner, but not in HeyA8-MDR. In in vivo experiments, axitinib significantly decreased tumor weight in xenograft models of drug-sensitive (A2780), and clear cell carcinoma (RMG1) and PDX models for platinum sensitive EOC compared to control, but was not effective in drug-resistant cell line (HeyA8-MDR) or heavily pretreated refractory PDX model. Axitinib showed significant anti-cancer effects in drug-sensitive or clear cell EOC cells via inhibition of VEGFR signals associated with cell proliferation, apoptosis and migration, but not in drug-resistant cells.

Corticosteroids have been empirically administered to reduce the rate of acute respiratory distress syndrome (ARDS) after esophagectomy. However, their efficacy remains controversial, and corticosteroids may increase the risk of graft dehiscence and infection, which are major concerns after esophagectomy. Therefore, we compared the incidence of composite complications (ARDS, graft dehiscence and infection) after esophagectomy between patients who received a preventive administration of corticosteroids and those who did not. All patients who underwent esophagectomy from 2010 to 2015 at a tertiary care university hospital were reviewed retrospectively (n = 980). Patients were divided into Steroid (n = 120) and Control (n = 860) groups based on the preventive administration of 100 mg hydrocortisone during surgery. The primary endpoint was the incidence of composite complications. The incidence of composite complications was not different between the Control and Steroid groups (17.4% vs. 21.7% respectively; P = 0.26). The incidence rates of complications in each category were not different between the Control and Steroid groups: ARDS (3.8% vs. 5.0%; P = 0.46), graft dehiscence (4.8% vs. 6.7%; P = 0.37), and infection (12.8% vs. 15.8%; P = 0.36). Propensity score matching revealed that composite complications (20.0% vs. 21.7%; P = 0.75), ARDS (4.3% vs. 5.2%; P = 0.76) and infection (16.5% vs. 15.7%; P = 0.86) were not different between the Control and Steroid group, but the incidence of graft dehiscence was higher in the Steroid group than in the Control group (0.9% vs. 7.0%; P = 0.0175). In conclusions, the preventive use of corticosteroids did not reduce the incidence of ARDS, but may be related to an increased incidence of graft dehiscence. Therefore, routine administration of corticosteroids to prevent ARDS is not recommended in esophagectomy.

The transient silencing effects currently demonstrated by nonviral siRNA delivery systems limit the therapeutic utility of RNAi, but it remains a technical challenge to prolong duration of gene silencing. We have developed a T7 autogene-based hybrid mRNA/DNA system to enable long-term expression of shRNA in cytoplasm in vitro and in vivo. This hybrid mRNA/DNA system consists of T7 polymerase (T7pol) mRNA, pT7/shRNA-encoding DNA fragment and T7 autogene plasmid, and it can generate higher levels of T7pol proteins, compared to pCMV-triggering T7 autogene system, especially without the need of nuclear entry of any gene. A large amount of T7pol proteins produced are used to induce pT7-driven expression of shRNA in cytoplasm, and through cellular processing of RNA hairpins, mature siRNAs are generated for more than 13 days. We here demonstrate that a single liposomal delivery of this hybrid system leads to the long-term silencing effects in vitro and in vivo, in contrast to the conventional siRNA methods relying on the repeated administrations every 2 or 3 days. These sustainable shRNA expression properties in cytoplasm can provide an efficient strategy to address the limitations caused by shRNA-encoding plasmid DNA systems such as low nuclear entry efficiency and short-term silencing effect. The development of long-term shRNA expression system in vivo could scale down administration frequency of RNAi therapeutics in the treatment of chronic diseases, thereby increasing its clinical utility.

The inherent or acquired resistance to paclitaxel and cisplatin, which are commonly used chemotherapeutic agents for ovarian cancer treatment, remains an important issue in chemotherapy of multidrug resistant ovarian cancer. Currently, it is still challenging to deal with the recurrent or advanced stage ovarian cancer. When drug efflux and anti-apoptotic pathways are highly interdependent and also involved in developing the resistance of multidrug resistant ovarian cancer, simultaneous inhibition of both pathways represents the potential targets to enhance the efficacy of chemotherapy. Here, we introduce PLGA nanoparticles system as a "dual RNAi delivery system" to contain both MDR1 and BCL2 siRNA, which is designed for simultaneous inhibition of drug efflux and cell death defense pathways. In the present studies, siRNA-loaded PLGA nanoparticles efficiently elicit the simultaneous suppression of both genes, which consequently shows more enhanced drug-sensitivity than sole suppression of drug efflux or anti-apoptosis in the resistant ovarian cancer cells, owing to the interdependence of both pathways. Our siRNA-loaded PLGA nanoparticles for co-delivering MDR1 and BCL2 siRNA provide an efficient combination therapy strategy to overcome the chemoresistance of paclitaxel and cisplatin on the paclitaxel-resistant SKOV3-TR and cisplatin-resistant A2780-CP20 ovarian cancer respectively.

Insulin-like growth factor-binding protein 5 (IGFBP-5) plays a role in cell growth, differentiation, and apoptosis. In this study, we found that IGFBP5 was markedly downregulated in ovarian cancer tissue. We investigated the functional significance of IGFBP-5 as a tumor suppressor. To determine functional regions of IGFBP-5, truncation mutants were prepared and were studied the effect on tumor growth. Expression of C-terminal region of IGFBP-5 significantly decreased tumor growth in an ovarian cancer xenograft. A peptide derived from the C-terminus of IGFBP-5 (BP5-C) was synthesized to evaluate the minimal amino acid motif that retained anti-tumorigenic activity and its effect on angiogenesis was studied. BP5-C peptide decreased the expression of VEGF-A and MMP-9, phosphorylation of Akt and ERK, and NF-kB activity, and inhibited angiogenesis in in vitro and ex vivo systems. Furthermore, BP5-C peptide significantly decreased tumor weight and angiogenesis in both ovarian cancer orthotopic xenograft and patient-derived xenograft mice. These results suggest that the C-terminus of IGFBP-5 exerts anti-cancer activity by inhibiting angiogenesis via regulation of the Akt/ERK and NF-kB-VEGF/MMP-9 signaling pathway, and might be considered as a novel angiogenesis inhibitor for the treatment of ovarian cancer.

Dentritic cell (DC)-based cancer immunotherapy faces challenges in both efficacy and practicality. However, DC-based vaccination requires multiple injections and elaborates ex vivo manipulation, which substantially limits their use. Therefore, we sought to develop a chitosan nanoparticle (CH-NP)-based platform for the next generation of vaccines to bypass the ex vivo manipulation and induce immune responses via active delivery of polyinosinic-polycytidylic acid sodium salt (poly I:C) to target Toll-like receptor 3 (TLR3) in endosomes. We developed CH-NPs encapsulating ovalbumin (OVA) as a model antigen and poly I:C as the adjuvant in an ionic complex. These CH-NPs showed increased in vivo intracellular delivery to the DCs in comparison with controls after injection into tumor-bearing mice, and promoted DC maturation, leading to emergence of antigen-specific cytotoxic CD8+ T cells. Finally, the CH-NPs showed significantly greater antitumor efficacy in EG.7 and TC-1 tumor-bearing mice compared to the control (p < 0.01). Taken together, these data show that the CH-NP platform can be used as an immune response modulatory vaccine for active cancer immunotherapy without ex vivo manipulation, thus resulting in increased anticancer efficacy.

Incorporating multiple copies of two RNAi molecules into a single nanostructure in a precisely controlled manner can provide an efficient delivery tool to regulate multiple gene pathways in the relation of mutual dependence. Here, we show a RNA nanotechnology platform for a two-in-one RNAi delivery system to contain polymeric two RNAi molecules within the same RNA nanoparticles, without the aid of polyelectrolyte condensation reagents. As our RNA nanoparticles lead to the simultaneous silencing of two targeted mRNAs, of which biological functions are highly interdependent, combination therapy for multi-drug resistance cancer cells, which was studied as a specific application of our two-in-one RNAi delivery system, demonstrates the efficient synergistic effects for cancer therapy. Therefore, this RNA nanoparticles approach has an efficient tool for a simultaneous co-delivery of RNAi molecules in the RNAi-based biomedical applications, and our current studies present an efficient strategy to overcome multi-drug resistance caused by malfunction of genes in chemotherapy.