Comparative analysis of long-term outcomes in thoracoabdominal aortic aneurysm repair between Marfan syndrome patients and non-Marfan syndrome patients.

BACKGROUND: A consensus on the management of thoracoabdominal aortic aneurysm (TAAA) in patients with Marfan syndrome (MFS) has not yet been established. This study aimed to compare the long-term outcomes after open TAAA repair in patients with and without MFS. METHODS: This retrospective study examined 230 consecutive patients who underwent TAAA repair between 2012 and 2022, including of 69 MFS patients and 161 non-MFS patients. The primary endpoint was long-term mortality. The secondary endpoint was a composite of early adverse events, including early mortality, permanent stroke, permanent paraplegia, permanent renal failure, and reoperation. Univariable and multivariable logistic regression analyses were used to assess the impact of MFS on early composite adverse events, and univariable and multivariable Cox proportional hazards models were constructed to evaluate the association between MFS and overall mortality. RESULTS: Compared with non-MFS patients, MFS patients were younger (mean, 31.9 ± 8.5 years vs 44.8 ± 12.3 years; P < .001), had less comorbid coronary artery disease (0 vs 8.1%; P = .034), more frequently underwent Crawford extent III repair (56.5% vs 34.8%; P = .002) and applied normothermic iliac perfusion (91.3% vs 81.4%; P = .057). There was no significant difference in the rate of early composite adverse events between the MFS and non-MFS groups (23.2% vs 14.3%; P = .099), which was verified by multivariable logistic regression analyses with multiple models. Overall mortality was significantly lower in the MFS group compared to the non-MFS group (P = .026, log-rank test), with 1-, 5-, and 10-year cumulative mortality of 4.4% versus 8.7%, 8.1% versus 17.2%, and 20.9% versus 36.4%, respectively. Multivariable Cox regression analyses across different models further confirmed MFS as a significant protective factor for overall mortality (model 1: hazard ratio [HR], 0.31; 95% confidence interval [CI] 0.13-0.73; P = .007; model 2: HR, 0.32, 95% CI, 0.13-0.75; P = .009; model 3: HR, 0.38; 95% CI, 0.15-0.95; P = .039). CONCLUSIONS: Despite varying risk profiles, MFS patients undergoing open TAAA repair can achieve comparable or even superior outcomes to non-MFS patients with tailored surgical strategies, meticulous perioperative care, and close follow-up surveillance, especially in the long term.

Risk Factors of Thrombocytopenia After Cardiac Surgery with Cardiopulmonary Bypass.

INTRODUCTION: Postoperative thrombocytopenia is common in cardiac surgery with cardiopulmonary bypass, and its risk factors are unclear. METHODS: This retrospective study enrolled 3,175 adult patients undergoing valve surgeries with cardiopulmonary bypass from January 1, 2017 to December 30, 2018 in our institute. Postoperative thrombocytopenia was defined as the first postoperative platelet count below the 10th quantile in all the enrolled patients. Outcomes between patients with and without postoperative thrombocytopenia were compared. The primary outcome was in-hospital mortality. Risk factors of postoperative thrombocytopenia were assessed by logistic regression analysis. RESULTS: The 10th quantile of all enrolled patients (75×109/L) was defined as the threshold for postoperative thrombocytopenia. In-hospital mortality was comparable between thrombocytopenia and non-thrombocytopenia groups (0.9% vs. 0.6%, P=0.434). Patients in the thrombocytopenia group had higher rate of postoperative blood transfusion (5.9% vs. 3.2%, P=0.014), more chest drainage volume (735 [550-1080] vs. 560 [430-730] ml, P<0.001), and higher incidence of acute kidney injury (12.3% vs. 4.2%, P<0.001). Age > 60 years (odds ratio [OR] 2.25, 95% confidence interval [CI] 1.345-3.765, P=0.002], preoperative thrombocytopenia (OR 18.671, 95% CI 13.649-25.542, P<0.001), and cardiopulmonary bypass time (OR 1.088, 95% CI 1.059-1.117, P<0.001) were positively independently associated with postoperative thrombocytopenia. Body surface area (BSA) (OR 0.247, 95% CI 0.114-0.538, P<0.001) and isolated mitral valve surgery (OR 0.475, 95% CI 0.294-0.77) were negatively independently associated with postoperative thrombocytopenia. CONCLUSION: Positive predictors for thrombocytopenia after valve surgery included age > 60 years, small BSA, preoperative thrombocytopenia, and cardiopulmonary bypass time. BSA and isolated mitral valve surgery were negative predictors.

Does methylprednisolone provide protective effect in total aortic arch replacement requiring hypothermia circulatory arrest and selective cerebral perfusion?

BACKGROUND: Glucocorticoids (GC)were applied in total aortic arch replacement (TAAR) at various dosages in many centers, but with limited evidence. METHODS: The retrospective study was aimed to evaluate whether methylprednisolone was associated with better postoperative outcomes in patients undergoing TAAR. Patients undergoing TAAR with moderate hypothermia and selective cerebral perfusion between 2017.1 to 2018.12 in Fuwai hospital were classified into three groups according to doses of methylprednisolone given in the surgery: large-GC group (1500-3000 mg); medium-GC group (500-1000 mg) and no-GC group (0 mg). Postoperative outcomes were compared among three groups. Multivariable analysis was performed to identify the association of methylprednisolone with outcomes. RESULTS: Three hundred twenty-eight patients were enrolled. Two hundred twenty-eight were in the large-GC group, 34 were in the medium-GC group, and 66 were in the no-GC group. The incidences of major adverse outcomes in large-GC, medium-GC and no-GC groups were 22.8%, 17.6% and 18.2%, respectively, with no statistical difference. A significant difference was observed in post-cardiopulmonary bypass (CPB) fresh frozen plasma (FFP) transfusion (p < .001) and chest drainage volume (p < .001). Multivariable analysis demonstrated that methylprednisolone was not associated with better outcomes (p = .455), while large doses of methylprednisolone were significantly associated with excessive chest drainage (over 2000 mL) [OR (99% CI) 4.282 (1.66-11.044), p < .001] and excessive post-CPB FFP transfusion (over 400 mL) [OR (99% CI) 2.208 (1.027-4.747), p = .008]. CONCLUSIONS: Large doses of methylprednisolone (1500-3000 mg) did not show a protective effect in TAAR with moderate hypothermia arrest plus selective cerebral perfusion and might increase postoperative bleeding and FFP transfusion.

Risk Factors of Thrombocytopenia After Cardiac Surgery with Cardiopulmonary Bypass

ABSTRACT Introduction: Postoperative thrombocytopenia is common in cardiac surgery with cardiopulmonary bypass, and its risk factors are unclear. Methods: This retrospective study enrolled 3,175 adult patients undergoing valve surgeries with cardiopulmonary bypass from January 1, 2017 to December 30, 2018 in our institute. Postoperative thrombocytopenia was defined as the first postoperative platelet count below the 10th quantile in all the enrolled patients. Outcomes between patients with and without postoperative thrombocytopenia were compared. The primary outcome was in-hospital mortality. Risk factors of postoperative thrombocytopenia were assessed by logistic regression analysis. Results: The 10th quantile of all enrolled patients (75×109/L) was defined as the threshold for postoperative thrombocytopenia. In-hospital mortality was comparable between thrombocytopenia and non-thrombocytopenia groups (0.9% vs. 0.6%, P=0.434). Patients in the thrombocytopenia group had higher rate of postoperative blood transfusion (5.9% vs. 3.2%, P=0.014), more chest drainage volume (735 [550-1080] vs. 560 [430-730] ml, P<0.001), and higher incidence of acute kidney injury (12.3% vs. 4.2%, P<0.001). Age > 60 years (odds ratio [OR] 2.25, 95% confidence interval [CI] 1.345-3.765, P=0.002], preoperative thrombocytopenia (OR 18.671, 95% CI 13.649-25.542, P<0.001), and cardiopulmonary bypass time (OR 1.088, 95% CI 1.059-1.117, P<0.001) were positively independently associated with postoperative thrombocytopenia. Body surface area (BSA) (OR 0.247, 95% CI 0.114-0.538, P<0.001) and isolated mitral valve surgery (OR 0.475, 95% CI 0.294-0.77) were negatively independently associated with postoperative thrombocytopenia. Conclusion: Positive predictors for thrombocytopenia after valve surgery included age > 60 years, small BSA, preoperative thrombocytopenia, and cardiopulmonary bypass time. BSA and isolated mitral valve surgery were negative predictors.

An Agreement Study Between Point-of-Care and Laboratory Activated Partial Thromboplastin Time for Anticoagulation Monitoring During Extracorporeal Membrane Oxygenation.

Background: Laboratory activated partial thromboplastin time (LAB-aPTT) is a widely used laboratory assay for monitoring unfractionated heparin (UFH) therapy during extracorporeal membrane oxygenation (ECMO). But LAB-aPTT is confined to a central laboratory, and the procedure is time-consuming. In comparison, point-of-care aPTT (POC-aPTT) is a convenient and quick assay, which might be a promising method for anticoagulation monitoring in ECMO. This study was aimed to evaluate the agreement between POC-aPTT (hemochron Jr. Signature instruments) and LAB-aPTT for anticoagulation monitoring in adult ECMO patients. Methods: Data of ECMO-supported adult patients anticoagulated with UFH in our institute from January 2017 to December 2020 was retrospectively reviewed. POC-aPTT and LAB-aPTT results measured simultaneously were paired and included in the analysis. The correlation between POC-aPTT and LAB-aPTT was assessed using Spearman's correlation coefficient. Bias between POC-aPTT and LAB-aPTT were described with the Bland-Altman method. Influence factors for bias were identified using multinomial logistic regression analysis. Results: A total 286 pairs of aPTT results from 63 patients were included in the analysis. POC-aPTT and LAB-aPTT correlated weakly (r = 0.385, P < 0.001). The overall bias between POC-aPTT and LAB-aPTT was 7.78 [95%CI (-32.49, 48.05)] s. The overall bias between POC-aPTT and LAB-aPTT ratio (to normal value) was 0.54 [95%CI (-0.68, 1.76)]. A higher plasma fibrinogen level [OR 1.353 (1.057, 1.733), P = 0.017] was associated with a higher chance of POC-aPTT underestimating LAB-aPTT. While a lower plasma fibrinogen level [OR 0.809 (0.679, 0.963), P = 0.017] and lower UFH rate [OR 0.928 (0.868, 0.992), P = 0.029] were associated with a higher chance of POC-aPTT overestimating LAB-aPTT. Conclusion: The present study showed poor agreement between POC-aPTT and LAB-aPTT. POC-aPTT was not suitable for anticoagulation monitoring in adult ECMO patients.

Outcomes from adult veno-arterial extracorporeal membrane oxygenation in a cardiovascular disease center from 2009 to 2019.

INTRODUCTION: Extracorporeal membrane oxygenation (ECMO) is an imperative short-term cardiopulmonary support device now. We aimed to provide a single-center experience of veno-arterial (V-A) ECMO management and identify the risk factors of in-hospital mortality. METHODS: We conducted a retrospective review of adult patients who received V-A ECMO between 2009 and 2019 in a cardiovascular disease center. The risk factor analysis of in-hospital mortality was conducted. RESULTS: The study reviewed 236 patients, with an overall survival rate of 68.2%. The survivors' blood lactate concentration is significantly lower than non-survivors [7.4 (7.8) vs 11.1 (9.7), p = 0.002]. Patients who received heart transplantation were with higher in-hospital survival rate. Survivors developed less hepatic dysfunction, acute kidney injury and myocardial damage [23 (14.3%) vs 19 (25.3%), p = 0.039; 81 (50.3%) vs 51 (68%), p = 0.011; 24 (14.9%) vs 22 (29.3%), p = 0.009, respectively], with higher rate of continuous renal replacement therapy (CRRT) [56 (34.8%) vs 53 (70.7%), p < 0.001]. Fewer survivors' 24 hours and total chest drainage was over 1000 mL, and the rate of re-exploration as well as red blood cell and platelet transfusion were lower in survivors. In multivariate analysis, female, pre-ECMO blood lactate concentration, hyperlipidemia, CRRT, and 24 hours chest drainage ⩾ 1000 mL were risk factors of early mortality. CONCLUSIONS: By providing a general description of V-A ECMO practice at a single-center in China. Post-heart transplant graft failure was associated with numerically, the greatest survival in our practice. Furthermore, female sex, pre-ECMO blood lactate concentration, hyperlipidemia, CRRT, and high blood loss in chest drains are predictors of mortality in patients who undergo V-A ECMO.

Air in extracorporeal membrane oxygenation: can never be overemphasized.

INTRODUCTION: Air in extracorporeal membrane oxygenation circuit may lead to deleterious consequence. CASE REPORT: Three cases of air in extracorporeal membrane oxygenation were presented. Air was introduced from right jugular venous sheath during percutaneous septal repair, pulmonary artery catheter during intensive care unit, and sewing holes on atrial wall during surgery respectively. Accidents in Case 2 and Case 3 were successfully managed, while Case 1 was suspected of cerebral air embolism through transseptal right-to-left shunt. DISCUSSION: With extracorporeal membrane oxygenation being widely applied in more clinical settings, especially in catheterization lab, risks of air in extracorporeal membrane oxygenation increase. More attention should be paid to patients with communication between right and left heart system, especially in situations when venous accesses' exposure to air could not be avoided. CONCLUSION: Air in the extracorporeal membrane oxygenation circuit should never be overemphasized, especially during special procedures.

Oncogenic TRIM37 Links Chemoresistance and Metastatic Fate in Triple-Negative Breast Cancer.

The majority of clinical deaths in patients with triple-negative breast cancer (TNBC) are due to chemoresistance and aggressive metastases, with high prevalence in younger women of African ethnicity. Although tumorigenic drivers are numerous and varied, the drivers of metastatic transition remain largely unknown. Here, we uncovered a molecular dependence of TNBC tumors on the TRIM37 network, which enables tumor cells to resist chemotherapeutic as well as metastatic stress. TRIM37-directed histone H2A monoubiquitination enforces changes in DNA repair that rendered TP53-mutant TNBC cells resistant to chemotherapy. Chemotherapeutic drugs triggered a positive feedback loop via ATM/E2F1/STAT signaling, amplifying the TRIM37 network in chemoresistant cancer cells. High expression of TRIM37 induced transcriptomic changes characteristic of a metastatic phenotype, and inhibition of TRIM37 substantially reduced the in vivo propensity of TNBC cells. Selective delivery of TRIM37-specific antisense oligonucleotides using antifolate receptor 1-conjugated nanoparticles in combination with chemotherapy suppressed lung metastasis in spontaneous metastatic murine models. Collectively, these findings establish TRIM37 as a clinically relevant target with opportunities for therapeutic intervention. SIGNIFICANCE: TRIM37 drives aggressive TNBC biology by promoting resistance to chemotherapy and inducing a prometastatic transcriptional program; inhibition of TRIM37 increases chemotherapy efficacy and reduces metastasis risk in patients with TNBC.

The strategy of cardiopulmonary bypass for total aortic arch replacement and the frozen elephant trunk technique with aortic balloon occlusion.

OBJECTIVE: To investigate the use of the aortic balloon occlusion technique to assist total aortic arch replacement (TAR) with frozen elephant trunk (FET) to shorten the lower body circulatory arrest (CA) time and raise the nadir temperature during cardiopulmonary bypass. METHODS: This retrospective study reviewed consecutive patients that underwent aortic balloon occlusion to assist TAR with FET and patients that received conventional TAR with FET procedures. Preoperative characteristics, perioperative characteristics and postoperative outcomes were compared between the two groups. RESULTS: The study included130 patients treated with aortic balloon occlusion and 230 patients treated with conventional TAR with FET. The 30-day mortality rate was similar between the aortic balloon occlusion and conventional groups (4.62% versus 7.83%, respectively). Multivariate analysis showed that aortic balloon occlusion reduced the incidence of acute kidney injury, hepatic injury and red blood cell transfusion. The application of aortic balloon occlusion reduced the mean ± SD CA time from 17.24 ± 4.36 min to 6.33 ± 5.74 min, with the target nadir nasal temperature being increased from 25°C to 28°C. CONCLUSION: The aortic balloon occlusion technique achieved significant improvements in reducing complications, but this did not translate into lower 30-day mortality.

Laparoscopic gastrectomy using intracorporeally hand-sewn anastomosis of esophagojejunostomy, gastroduodenostomy, or gastrojejunostomy for gastric cancer.

Laparoscopic gastrectomy (LG) using intracorporeal anastomosis has recently become more prevalent due to the advancements of laparoscopic surgical instruments. However, intracorporeally hand-sewn anastomosis (IHSA) is still uncommon because of technical difficulties. In this study, we evaluated various types of IHSA following LG with respect to the technical aspects and postoperative outcomes.Seventy-six patients who underwent LG using IHSA for treatment of gastric cancer between September 2014 and June 2018 were enrolled in this study. We described the details of IHSA in step-by-step manner, evaluated the clinicopathological data and surgical outcomes, and summarized the clinical experiences.Four types of IHSA have been described: one for total gastrectomy (Roux-en-Y) and 3 for distal gastrectomy (Roux-en-Y, Billroth I, and Billroth II). The mean operation time and anastomotic time was 288.7 minutes and 54.3 minutes, respectively. Postoperative complications were observed in 13 patients. All of the patients recovered well with conservative surgical management. There was no case of conversion to open surgery, anastomotic leakage, or mortality.LG using IHSA was safe and feasible and had several advantages compared to mechanical anastomosis. The technique lengthened operating time, but this could be mitigated by increased surgical training and experience.

Perfusion management of aortic balloon occlusion technique in total arch replacement with frozen elephant trunk.

To ensure both cerebral and lower body perfusion during total arch replacement with frozen elephant trunk, aortic balloon occlusion technique has been applied in some cases at our institute. During the procedure, after stented elephant trunk is inserted into the true lumen of the descending aorta, an aortic balloon catheter is placed and inflated within the stented elephant trunk, occluding the orifice of descending aorta. Then, lower body perfusion is provided via femoral cannulae during distal aortic arch anastomosis. We describe the perfusion management strategy of the technique, elucidate intraoperative monitoring parameters, and clarify the feasibility of the method from the aspect of perfusion.

Combined gastroscopic and choledochoscopic transabdominal nasobiliary drainage.

Common bile duct (CBD) stones are a frequent problem in Chinese populations, and their incidence is particularly high in certain areas (Wang et al., 2013). In recent years, laparoscopic common bile duct exploration (LCBDE) and endoscopic retrograde cholangiopancreatography (ERCP) have been the main surgical procedures for CBD stones, although each has different advantages and disadvantages in the treatment of choledocholithiasis (Loor et al., 2017; Zhou et al., 2017). For patients with large stones, a dilated CBD, especially concurrent gallstones, LCBDE is the preferred and most economical minimally invasive procedure (Koc et al., 2013). However, a T-tube is often placed during LCBDE to prevent postoperative bile leakage; this is associated with problems such as bile loss, electrolyte disturbance, and decreased gastric intake (Martin et al., 1998). In addition, the T-tube usually must remain in place for more than a month, during which time the patient's quality of life is seriously compromised. Many skilled surgeons currently perform primary closure of the CBD following LCBDE, which effectively speeds up rehabilitation (Hua et al., 2015). However, even in sophisticated medical centers, the incidence of postoperative bile leakage still reaches ≥10% (Liu et al., 2017). Especially for a beginner, bile leakage remains a key problem (Kemp Bohan et al., 2017). Therefore, a safe and effective minimally invasive surgical approach to preventing bile leakage during primary closure of the CBD after LCBDE is still urgently needed.

Perfusion strategy and mid-term results of 58 consecutive pulmonary endarterectomy.

OBJECTIVE: The aim of this retrospective study was to review and report short-term and mid-term outcomes of pulmonary endarterectomy for chronic thromboembolic pulmonary hypertension at our institute in the recent 2 years and to describe perfusion strategy. METHODS: A total of 58 consecutive patients with chronic thromboembolic pulmonary hypertension underwent pulmonary endarterectomy under deep hypothermia circulatory arrest with an established perfusion practice between November 2015 and December 2017. Peri-operative data and patients' outcome were retrospectively analyzed. RESULTS: Mean pulmonary artery pressure was decreased (49 (40-56) mmHg vs 27 (20-31) mmHg, p < 0.001), and pulmonary vascular resistance (724 (538-1108) vs 206 (141-284) dyn second cm-5, p < 0.001) improved significantly after surgery. In-hospital mortality was 1.7% and postoperative complication rate was 27.6%. Antipsychotic medication of olanzapine was prescribed for 36 patients (62.1%), which was independently related to total deep hypothermic circulatory arrest time, postoperative blood potassium concentration, and hematocrit. The majority of patients recovered uneventfully with good mid-term cardiac function (New York Heart Association I-II: 98.1%) and neurological outcome (Glasgow Outcome Scale-Extended Upper Good Recovery: 74.1% and Lower Good Recovery: 20.3%). Mid-term neurological outcome was associated with post-pulmonary endarterectomy antipsychotic medication. CONCLUSION: Short-term and mid-term outcome after pulmonary endarterectomy was comparable to high-volume centers. Incidence of post-pulmonary endarterectomy delirium was relatively high and associated with mid-term neurological outcome. Total deep hypothermic circulatory arrest time, postoperative blood potassium concentration, and hematocrit were independent risk factors of postoperative olanzapine medication. More efforts and further research are required to optimize the neuroprotection of perfusion practice.

Effect of an intra-aortic balloon pump with venoarterial extracorporeal membrane oxygenation on mortality of patients with cardiogenic shock: a systematic review and meta-analysis†.

An intra-aortic balloon pump (IABP) concomitant with venoarterial extracorporeal membrane oxygenation (VA-ECMO) is frequently used to support patients with refractory cardiogenic shock (CS). Because of the lack of evidence of the adjunctive benefit, the goal of the study was to compare the effect of VA-ECMO plus IABP with that of VA-ECMO alone. Systematic searches were conducted to identify studies using PubMed, Embase, the Cochrane Library and the International Clinical Trials Registry Platform. Studies reporting on patients with adult CS treated with VA-ECMO plus IABP or VA-ECMO alone were identified and included. The primary outcome was in-hospital death. The secondary outcomes included neurological, gastrointestinal and limb-related complications. The study protocol was registered at PROSPERO (CRD42017069259). A total of 29 studies comprising 4576 patients were included. The pooled in-hospital deaths of patients on VA-ECMO were 1441/2285 (63.1%) compared with 1339/2291 (58.4%) for patients with adjunctive IABP. VA-ECMO plus IABP was associated with decreased in-hospital deaths [risk ratio (RR) 0.90; 95% confidence interval (CI) 0.85-0.95; P < 0.0001]. Moreover, IABP was related to decreased in-hospital deaths of patients with extracorporeal cardiopulmonary resuscitation, postcardiotomy CS and ischaemic heart disease (RR 0.78; 95% CI 0.64-0.95; P = 0.01; RR 0.91; 95% CI: 0.85-0.98; P = 0.008; RR 0.83; 95% CI 0.73-0.96, P = 0.009). Neurological, gastrointestinal and limb-related complications did not differ significantly between patients on ECMO with and without concurrent IABP. VA-ECMO plus IABP was associated with decreased in-hospital deaths in patients with CS.

Ultrafiltration and reinfusion of residual cardiopulmonary bypass pump blood: A prospective non-randomized controlled study.

The aim of the study was to investigate whether processing residual pump blood with ultrafiltration could increase the increment of hemoglobin after residual pump blood reinfusion and evaluate its influence on plasma-free hemoglobin (pFHb) level and postoperative renal function. Sixty adult patients undergoing elective cardiac surgery with cardiopulmonary bypass were assigned to 2 groups, based on pump blood processing strategy: ultrafiltration plus reinfusion (n = 30) or reinfusion (control; n = 30). Increment in hemoglobin and pFHb after reinfusion (ΔHgb, ΔpFHb), reinfusion volume, postoperative chest drainage volume (first 24 h), duration of mechanical ventilation, changes in serum creatinine, and prevalence of AKI were compared between the 2 groups. Higher levels of both ΔHgb and ΔpFHb were observed after reinfusion in the ultrafiltration group [ΔHgb 1.8 ± 1.1 g/dL vs. 1.2 ± 0.6 g/dL, P = 0.03, ΔpFHb 100 (0, 200) mg/L vs. 0 (-100, 0) mg/L, P = 0.03]. The reinfusion volume was lower in the ultrafiltration group [550 (325, 615) mL vs. 1000 (900, 1180) mL, P < 0.001]. No differences were found in postoperative chest drainage volume (first 24 h), duration of mechanical ventilation, changes in serum creatinine, and prevalence of AKI. Compared to the unprocessed group, ultrafiltration before reinfusion of residual pump blood improved the hemoglobin level and reduced volume loading. Despite an increase in pFHb, the processing procedure was not related to postoperative kidney injury.

Multifunctional Nanosystem for Targeted and Controlled Delivery of Multiple Chemotherapeutic Agents for the Treatment of Drug-Resistant Breast Cancer.

By targeting CD44 receptors, inhibiting multidrug resistance (MDR), controlling drug release, and synergistically inhibiting tumor growth, a multilayered nanosystem was developed to serve as a multifunctional platform for the treatment of drug-resistant breast cancers. The multilayer nanosystem is composed of a poly(lactic-co-glycolic acid) core, a liposome second layer, and a chitosan third layer. The chitosan-multilayered nanoparticles (Ch-MLNPs) can co-deliver three chemotherapeutic agents: doxorubicin (DOX), paclitaxel (PTX), and silybin. The three drugs are released from the multilayered NPs in a controlled and sequential manner upon internalization and localization in the cellular endosomes. The presence of a chitosan layer allows the nanosystem to target a well-characterized MDR breast cancer biomarker, the CD44s receptor. In vitro cytotoxicity study showed that the nanosystem loaded with triple drugs, DOX-PTX-silybin, resulted in better antitumor efficacy than the single-drug or dual-drug nano-formulations. Likely attributed to the MDR-inhibition effect of silybin, the co-delivered DOX and PTX exhibited a better synergistic effect on MDR breast cancer cells than on non-MDR breast cancer cells. The in vivo study also showed that the multilayered nanosystem promoted MDR inhibition and synergy between chemotherapeutic agents, leading to significant tumor reduction in a xenograft animal model. Ch-MLNPs reduced the tumor volume by fivefold compared to that of the control group without causing overt cytotoxicity.

A Nano-in-Nano Polymer-Dendrimer Nanoparticle-Based Nanosystem for Controlled Multidrug Delivery.

Codelivery of multiple chemotherapeutics with different action mechanisms is a promising strategy for cancer treatment. In this study, we developed a novel polymer-dendrimer hybrid nanoparticle-based nanosystem for efficient and controlled codelivery of two model chemotherapeutics, doxorubicin (DOX) and paclitaxel (PTX). The nanosystem was characterized to have a nano-in-nano structure with a size of around 150 nm. The model drugs could feasibly be loaded into the nanosystem ratiometrically with high drug-loading contents by controlling the feeding drug ratios. Also, the model drugs could be released from the nanosystem following a sequential release manner-specifically, quick PTX release and sustained DOX release. Acidic pH was found to enhance the release of both drugs. Moreover, the nanosystem was taken up by cancer cells rapidly and efficiently, and the delivered drugs could release sustainably and efficiently in cells to reach their action targets. In vitro cytotoxicity results demonstrated that, by optimizing drug ratios, the dual-drug-loaded nanosystem could result in better antitumor efficacy than the single-drug-loaded nanosystem or free dual-drug combination. Furthermore, the dual-drug-loaded nanosystem could induce significant changes in both the nucleus and tubulin patterns synergistically. All data suggest that the nano-in-nano polymer-dendrimer hybrid nanoparticle-based nanosystem is a promising candidate to achieve controlled multidrug delivery for effective combination cancer therapy.

Extended Septal Myectomy for Hypertrophic Obstructive Cardiomyopathy in Children and Adolescents.

Extended septal myectomy for children and adolescents with hypertrophic obstructive cardiomyopathy (HOCM) is a challenging procedure, and related data are currently limited. Our study objective was to assess the early outcomes in children and adolescents with HOCM after extended septal myectomy. From October 2007 to August 2015, 40 consecutive patients with HOCM underwent transaortic extended septal myectomy in Fuwai Hospital, Beijing, China. Patients clinical data were analyzed retrospectively. Mean age at the time of operation was 11.3 ± 4.3 (0.7-16.7) years. Mean body weight at the time of surgery was 40.8 ± 19.7 (4.3-92.0) kg. After myectomy, mean left ventricular outflow tract gradient decreased from 80.1 ± 33.8 to 14.7 ± 11.5 mmHg and mean degree of mitral regurgitation decreased from 1.9 ± 0.9 to 0.5 ± 0.5 (p < 0.001 for both). Concomitant surgical procedures were required in 13 patients (32.5 %). There was no early death. Residual systolic anterior motion and left ventricular outflow tract obstruction were reported in two and three patients, respectively. Moderate aortic regurgitation was found in one patient during a follow-up of 26.4 ± 15.1 months. Restrictive symptoms were improved in the patients with New York Heart Association functional class I or II. A 15.8-year-old patient died 16 months after operation. A permanent pacemaker was installed in one patient 3 months after operation. Extended septal myectomy is safe and effective in children and adolescents with HOCM, with excellent clinical and echocardiographic outcome at early follow-up.