Blinded, randomized trial of sonographer versus AI cardiac function assessment.

Artificial intelligence (AI) has been developed for echocardiography1-3, although it has not yet been tested with blinding and randomization. Here we designed a blinded, randomized non-inferiority clinical trial (ClinicalTrials.gov ID: NCT05140642; no outside funding) of AI versus sonographer initial assessment of left ventricular ejection fraction (LVEF) to evaluate the impact of AI in the interpretation workflow. The primary end point was the change in the LVEF between initial AI or sonographer assessment and final cardiologist assessment, evaluated by the proportion of studies with substantial change (more than 5% change). From 3,769 echocardiographic studies screened, 274 studies were excluded owing to poor image quality. The proportion of studies substantially changed was 16.8% in the AI group and 27.2% in the sonographer group (difference of -10.4%, 95% confidence interval: -13.2% to -7.7%, P < 0.001 for non-inferiority, P < 0.001 for superiority). The mean absolute difference between final cardiologist assessment and independent previous cardiologist assessment was 6.29% in the AI group and 7.23% in the sonographer group (difference of -0.96%, 95% confidence interval: -1.34% to -0.54%, P < 0.001 for superiority). The AI-guided workflow saved time for both sonographers and cardiologists, and cardiologists were not able to distinguish between the initial assessments by AI versus the sonographer (blinding index of 0.088). For patients undergoing echocardiographic quantification of cardiac function, initial assessment of LVEF by AI was non-inferior to assessment by sonographers.

Mechanisms of Sinoatrial Node Dysfunction in Heart Failure With Preserved Ejection Fraction.

BACKGROUND: The ability to increase heart rate during exercise and other stressors is a key homeostatic feature of the sinoatrial node (SAN). When the physiological heart rate response is blunted, chronotropic incompetence limits exercise capacity, a common problem in patients with heart failure with preserved ejection fraction (HFpEF). Despite its clinical relevance, the mechanisms of chronotropic incompetence remain unknown. METHODS: Dahl salt-sensitive rats fed a high-salt diet and C57Bl6 mice fed a high-fat diet and an inhibitor of constitutive nitric oxide synthase (Nω-nitro-L-arginine methyl ester [L-NAME]; 2-hit) were used as models of HFpEF. Myocardial infarction was created to induce HF with reduced ejection fraction. Rats and mice fed with a normal diet or those that had a sham surgery served as respective controls. A comprehensive characterization of SAN function and chronotropic response was conducted by in vivo, ex vivo, and single-cell electrophysiologic studies. RNA sequencing of SAN was performed to identify transcriptomic changes. Computational modeling of biophysically-detailed human HFpEF SAN was created. RESULTS: Rats with phenotypically-verified HFpEF exhibited limited chronotropic response associated with intrinsic SAN dysfunction, including impaired ß-adrenergic responsiveness and an alternating leading pacemaker within the SAN. Prolonged SAN recovery time and reduced SAN sensitivity to isoproterenol were confirmed in the 2-hit mouse model. Adenosine challenge unmasked conduction blocks within the SAN, which were associated with structural remodeling. Chronotropic incompetence and SAN dysfunction were also found in rats with HF with reduced ejection fraction. Single-cell studies and transcriptomic profiling revealed HFpEF-related alterations in both the "membrane clock" (ion channels) and the "Ca2+ clock" (spontaneous Ca2+ release events). The physiologic impairments were reproduced in silico by empirically-constrained quantitative modeling of human SAN function. CONCLUSIONS: Chronotropic incompetence and SAN dysfunction were seen in both models of HF. We identified that intrinsic abnormalities of SAN structure and function underlie the chronotropic response in HFpEF.

High-Throughput Single-Cell Proteomic Analysis of Organ-Derived Heterogeneous Cell Populations by Nanoflow Dual-Trap Single-Column Liquid Chromatography.

Identification and proteomic characterization of rare cell types within complex organ-derived cell mixtures is best accomplished by label-free quantitative mass spectrometry. High throughput is required to rapidly survey hundreds to thousands of individual cells to adequately represent rare populations. Here we present parallelized nanoflow dual-trap single-column liquid chromatography (nanoDTSC) operating at 15 min of total run time per cell with peptides quantified over 11.5 min using standard commercial components, thus offering an accessible and efficient LC solution to analyze 96 single cells per day. At this throughput, nanoDTSC quantified over 1000 proteins in individual cardiomyocytes and heterogeneous populations of single cells from the aorta.

Pure Laparoscopic Versus Open Right Hepatectomy in Live Liver Donors: A Propensity Score-matched Analysis.

OBJECTIVE: The aim of the study was to present the safety and feasibility of pure laparoscopic donor right hepatectomy (PLDRH) in comparison with those of conventional donor right hepatectomy. SUMMARY BACKGROUND DATA: Although the use of PLDRH is gradually spreading worldwide, its outcomes, including the long-term outcomes in both donors and recipients, have not yet been evaluated in a large comparative study. METHODS: We retrospectively reviewed the medical records of 894 donors who underwent living donor liver transplantation between January 2010 and September 2018 at Seoul National University Hospital. We performed 1:1 propensity score matching between the PLDRH and conventional donor right hepatectomy groups. Subsequently, 198 donor-recipient pairs were included in each group. RESULTS: The total operation time (P < 0.001), time to remove the liver (P < 0.001), and warm ischemic time (P < 0.001) were longer in the PLDRH group. None of the donors required intraoperative transfusion or experienced any irreversible disabilities or mortalities. The length of postoperative hospital stay was significantly shorter in the PLDRH group (P < 0.001). The rate of complications in donors was similar between the 2 groups. Although other complication rates in recipients were, however, similar, the rates of early (P = 0.019) and late (P < 0.001) biliary complications in recipients were higher in the PLDRH group. There was no significant difference in overall survival and graft survival between the 2 groups. CONCLUSIONS: PLDRH is feasible when performed at an experienced living donor liver transplantation center. Further studies on long-term recipient outcomes including biliary complications are needed to confirm the safety.

Yield precursor in primary creep of colloidal gels.

Colloidal gels under constant moderate stress flow only after a prolonged solid-like deformation. Predicting the time-dependent yielding of the gels would facilitate control of their mechanical stability and transport, but early detectable signs of such delayed solid-to-fluid transition remain unknown. We show that the shear rate of colloidal gels under constant stress can forecast an eventual yielding during the earliest stage of deformation known as primary creep. The shear rate before failure exhibits a characteristic power-law decrease as a function of time, distinct from the linear viscoelastic response. We model this early-stage behavior as a series of uncorrelated local plastic events that are thermally activated, which illuminates the exponential dependence of the yield time on the applied stress. By revealing underlying viscoplasticity, this precursor to yield in the macroscopic shear rate provides a convenient tool to predict the yielding of a gel well in advance of its actual occurrence.

Optimal Intervention for Initial Treatment of Anastomotic Biliary Complications After Right Lobe Living Donor Liver Transplantation.

Background: This study evaluated endoscopic retrograde cholangiopancreatography (ERCP) and percutaneous transhepatic biliary drainage (PTBD) as interventions for patients with anastomotic biliary complications (ABC) after living donor liver transplantation (LDLT). Methods: Prospectively collected data of patients who were diagnosed with ABC after LDLT between January 2013 and June 2017 were retrospectively reviewed. Results: There were 57 patients who underwent LDLT with a right liver graft using duct-to-duct biliary reconstruction and experienced ABC. Among the patients with RAD involvement, there were no significant differences in the intervention success (p = 0.271) and patency rates (p = 0.267) between ERCP and PTBD. Similarly, among the patients with RPD involvement, there were no significant differences in the intervention success (p = 0.148) and patency rates (p = 0.754) between the two procedures. Graft bile duct variation (p = 0.013) and a large angle between the recipient and graft bile duct (R-G angle) (p = 0.012) significantly increased the likelihood of failure of ERCP in the RAD. When the R-G angle was greater than 47.5°, the likelihood of ERCP failure increased. Conclusion: We recommend PTBD when graft bile duct variation is presented in patients with RAD involvement and/or when the R-G angle is greater than 47.5°.

Short-term therapy with anti-ICAM-1 monoclonal antibody induced long-term liver allograft survival in nonhuman primates.

Tolerance induction remains challenging following liver transplantation and the long-term use of immunosuppressants, especially calcineurin inhibitors, leads to serious complications. We aimed to test an alternative immunosuppressant, a chimeric anti-ICAM-1 monoclonal antibody, MD-3, for improving the outcomes of liver transplantation. We used a rhesus macaque liver transplantation model and monkeys were divided into three groups: no immunosuppression (n = 2), conventional immunosuppression (n = 4), and MD-3 (n = 5). Without immunosuppression, liver allografts failed within a week by acute rejection. Sixteen-week-long conventional immunosuppression that consisted of prednisolone, tacrolimus, and an mTOR inhibitor prolonged liver allograft survival; however, recipients died of acute T cell-mediated rejection (day 52), chronic rejection (days 62 and 66), or adverse effects of mTOR inhibitor (day 32). In contrast, 12-week-long MD-3 therapy with transient conventional immunosuppression in the MD-3 group significantly prolonged the survival of liver allograft recipients (5, 96, 216, 412, 730 days; p = .0483). MD-3 effectively suppressed intragraft inflammatory cell infiltration, anti-donor T cell responses, and donor-specific antibody with intact anti-cytomegalovirus antibody responses. However, this regimen ended in chronic rejection. In conclusion, short-term therapy with MD-3 markedly improved liver allograft survival to 2 years without maintenance of immunosuppressant. MD-3 is therefore a promising immune-modulating agent for liver transplantation.

Demarcating the Exact Midplane of the Liver Using Indocyanine Green Near-Infrared Fluorescence Imaging During Laparoscopic Donor Hepatectomy.

Indocyanine green (ICG) near-infrared fluoroscopy has been recently implemented in pure laparoscopic donor hepatectomy (PLDH). This study aims to quantitatively evaluate the effectiveness of ICG fluoroscopy during liver midplane dissection in PLDH and to demonstrate that a single injection of ICG is adequate for both midplane dissection and bile duct division. Retrospective analysis was done with images acquired from recordings of PLDH performed without ICG (pre-ICG group) from November 2015 to May 2016 and with ICG (post-ICG group) from June 2016 to May 2017. 30 donors from the pre-ICG group were compared with 46 donors from the post-ICG group. The operation time was shorter (P = 0.002) and postoperative peak aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels were lower (P = 0.031 and P = 0.019, respectively) in the post-ICG group than the pre-ICG group. Within the post-ICG group, the color intensity differences between the clamped versus nonclamped regions in the natural, black-and-white, and fluorescent modes were 39.7 ± 36.2, 89.6 ± 46.9, and 19.1 ± 36.8 (mean ± SD, P < 0.001), respectively. The luminosity differences were 37.2 ± 34.5, 93.8 ± 32.1, and 26.7 ± 25.7 (P < 0.001), respectively. Meanwhile, the time from when ICG was injected to when the near-infrared camera was turned on for bile duct visualization was 85.6 ± 25.8 minutes. All grafts received from the 46 donors were successfully transplanted. In conclusion, ICG fluoroscopy helps to reduce operation time and lower postoperative AST/ALT levels. ICG injection visualized with black-and-white imaging is most effective for demarcating the liver midplane during PLDH. A single intravenous injection of ICG is sufficient for midplane dissection as well as bile duct division.

Dextroplantation of Left Liver Graft in Infants.

The position of the left side liver graft is important, and it could lead to complications of the hepatic vein (HV) and portal vein (PV), especially in a small child using a variant left lateral section (vLLS) graft. The purpose of this study was to evaluate the outcome of a novel technique for the implantation of a vLLS graft to the right side (dextroplantation) in infants. For 3 years, 10 consecutive infants underwent dextroplantation using a vLLS graft (group D). The graft was implanted to the right side of the recipient after 90° counterclockwise rotation; the left HV graft was anastomosed to inferior vena cava using the extended right and middle HV stump, and PV was reconstructed using oblique anastomosis without angulation. Surgical outcomes were compared with the historical control group (n = 17, group C) who underwent conventional liver transplantation using a vLLS during infancy. Group D recipients were smaller than group C (body weight <6 kg: 50.0% versus 11.8%; P = 0.03). The rate of graft-to-recipient weight ratio >4% was higher in group D (60.0%) than C (11.8%; P = 0.01). Surgical drains were removed earlier in group D than in group C (15 versus 18 postoperative days [PODs]; P = 0.048). Each group had 1 PV complication (10.0% versus 5.9%); no HV complication occurred in group D, but 3 HV complications (17.6%) occurred in group C (P > 0.05). Hospital stay was shorter in group D than in group C (20 versus 31 PODs; P = 0.02). Dextroplantation of a vLLS graft, even a large-for-size one, was successful in small infants without compromising venous outcomes, compared with conventional vLLS transplantation. We could remove the surgical drains earlier and reduce hospital stays in cases of dextroplantation.

Complications of polytetrafluoroethylene graft use in middle hepatic vein reconstruction in living donor liver transplantation: a retrospective, single-centre, long-term, real-world experience.

In living donor liver transplantation (LDLT) of the right lobe, polytetrafluoroethylene (PTFE) grafts may be used for anterior drainage. This study aimed to determine the risk factors of PTFE graft-associated complications. Data from patients who underwent LDLT of the right lobe with middle hepatic vein reconstruction using PTFE grafts between January 2005 and December 2012 were retrospectively reviewed. Among 360 patients, PTFE graft-associated complications occurred in 17 patients (group B) (4.7%); recipients without these complications comprised group A (95.3%). The 1-, 6- and 12-month patency rates were significantly lower in group B (P < 0.001, P = 0.002 and P = 0.007). In group B, eight patients (47.1%) required surgical intervention, three patients (17.6%) suffered from infectious complications, and 14 patients (82.4%) experienced PTFE graft migration into the adjacent organs, namely the common bile duct (n = 3, 17.6%), stomach (n = 1, 5.9%), duodenum (n = 5, 29.4%) and jejunum (n = 5, 29.4%). The proportion of recipients who underwent hepaticojejunostomy, had abdominal adhesions and received interventions in/around the liver after LDLT was higher in group B (P < 0.001). Although the incidence of PTFE graft-associated complication is low, close long-term follow-up is needed, especially in patients with risk factors.

Donor wound satisfaction after living-donor liver transplantation in the era of pure laparoscopic donor hepatectomy.

BACKGROUND: Donor safety and cosmetic outcome are the main concerns raised by most living-donors. Pure laparoscopic living-donor hepatectomy (PLLDH) can provide the balance between those concerns. No studies evaluated the donors' satisfaction after PLLDH. The aim of this study is to evaluate the donors' satisfaction after PLLDH compared with donors who underwent open approach. METHODS: We randomly assigned a questionnaire (Donor satisfaction questionnaire) to the donors, operated between 2011 and 2017, during their follow-up visits in the outpatient clinic. Donors who responded to the questionnaire were included in our study. Donors were divided into 3 groups: L group (conventional inverted L incision), M group (midline incision), and PL group (laparoscopic approach). RESULTS: 149 donors were included in our study. L group included 60 donors (40.3%), M group included 39 patients (26.2%), and PL group included 50 patients (33.5%). There were no significant differences between the groups regarding preoperative and perioperative outcomes apart from shorter operation time in PL group and higher wound infection in M group. Body image scale was significantly better in PL group (p = 0.001). Cosmetic scale was significantly higher in PL group (p = 0.001). Regarding self-confidence scale, it was significantly higher in PL group (p = 0.001). There was no significant difference between the groups regarding the sense of dullness or numbness on the scar (p = 0.113). CONCLUSION: PLLDH is safe and feasible for living-donor hepatectomy. Donors operated by pure laparoscopic approach have better satisfaction scores compared to conventional open approach.

Pure Laparoscopic Versus Open Left Hepatectomy Including the Middle Hepatic Vein for Living Donor Liver Transplantation.

Pure laparoscopic donor hepatectomy (PLDH) has become increasingly accepted in the era of minimally invasive surgeries. However, the outcomes of pure laparoscopic donor left hepatectomy (PLDLH) are relatively less known than for left lateral sectionectomy or right hepatectomy. This study aimed to report our experience with and the outcomes of PLDLH including the middle hepatic vein (MHV) and to compare these outcomes with conventional donor left hepatectomy (CDLH). The medical records of living liver donors between January 2010 and January 2018 at Seoul National University Hospital were retrospectively reviewed. Donors who underwent left hepatectomy including the MHV were included. To minimize selection bias, donors who underwent CDLH after the initiation of the PLDH program were excluded. Finally, there were 18 donors who underwent CDLH and 8 who underwent PLDLH. The median (interquartile range [IQR]) warm ischemia time (11 [10-16] minutes versus 4 [2-7] minutes; P = 0.001) was longer in the PLDLH group than the CDLH group. The total operation time (333 [281-376] minutes versus 265 [255-308] minutes; P = 0.09) and time to remove the liver (245 [196-276] minutes versus 182 [172-205] minutes; P = 0.08) were also longer in PLDLH although not statistically significant. The length of postoperative hospital stay was significantly shorter in the PLDLH group (7 [7-8] days versus 9 [8-10] days; P = 0.01). There were no postoperative complications in the PLDLH group. The rate of complications in recipients was similar in both groups. In conclusion, PLDLH including the MHV appears to be safe and feasible. Further analysis including longterm outcomes is needed.

Emergence of Multiscale Dynamics in Colloidal Gels.

To gain insight into the kinetics of colloidal gel evolution at low particle volume fractions ϕ, we utilize differential dynamic microscopy to investigate particle aggregation, geometric percolation, and the subsequent transition to nonergodic dynamics. We report the emergence of unexpectedly rich multiscale dynamics upon the onset of nonergodicity, which separates the wave vectors q into three different regimes. In the high-q domain, the gel exhibits ϕ-independent internal vibrations of fractal clusters. The intermediate-q domain is dominated by density fluctuations at the length scale of the clusters, as evidenced by the q independence of the relaxation time τ. In the low-q domain, the scaling of τ as q^{-3} suggests that the network appears homogeneous. The transitions between these three regimes introduce two characteristic length scales, distinct from the cluster size.

Different prognostic factors and strategies for early and late recurrence after adult living donor liver transplantation for hepatocellular carcinoma.

BACKGROUND: Some patients with hepatocellular carcinoma (HCC) recurrence after LT show good long-term survival. We aimed to determine the prognostic factors affecting survival after recurrence and to suggest treatment strategies. METHODS: Between January 2000 and December 2015, 532 patients underwent adult living donor liver transplantation (LDLT) for HCC. Among these, 92 (17.3%) who experienced recurrence were retrospectively reviewed. RESULTS: The 1-, 3-, and 5-year survival rates after recurrence were 59.5%, 23.0%, and 11.9%, respectively. In multivariate analysis, time to recurrence >6 months and surgical resection after recurrence were related to longer survival after recurrence, while multi-organ involvement at the time of primary recurrence was related to poorer survival. We classified patients into early (≤6 months) and late (>6 months) recurrence groups. In the early recurrence group, tumor size >5 cm in the explant liver, liver as the first detected site of recurrence, and multiple organ involvement at primary recurrence were related to survival on multivariate analysis. In the late recurrence group, mammalian target of rapamycin inhibitor (mTORi) usage and multi-organ involvement were significantly associated with the prognosis on multivariate analysis. CONCLUSIONS: Various therapeutic approaches are needed depending on the period of recurrence after LT and multiplicity of involved organs.

The learning curve in pure laparoscopic donor right hepatectomy: a cumulative sum analysis.

BACKGROUND: Although the use of pure laparoscopic donor hepatectomy (PLDH) is increasingly common, it remains limited to a few experienced centers and no data on the learning curve are currently available. The aim of this study is to evaluate the learning curve associated with the use of pure laparoscopic donor right hepatectomy (PLDRH). METHODS: Data from donors undergoing PLDRH performed by a single surgeon between November 2015 and October 2017 were retrospectively reviewed. The learning curve was evaluated using the cumulative sum (CUSUM) method based on duration of surgery. RESULTS: Of 100 donors evaluated, none required transfusion or conversion to open hepatectomy and no irreversible disability or mortality was reported. The mean operative time was 320.7 ± 51.8 min, and all grafts were successfully transplanted. The CUSUM analysis demonstrated a learning curve of approximately 60 cases of PLDRH. Estimated total liver volume > 1400 cm3 and double portal vein orifices were seen to be risk factors for longer surgery time. Having adjusted for case mix with these factors, the risk-adjusted CUSUM analysis demonstrated a learning curve of 65-70 cases of PLDRH. CONCLUSIONS: In conclusion, PLDRH is a feasible and safe procedure with a learning curve of 65-70 cases.

Pure laparoscopic donor right hepatectomy: perspectives in manipulating a flexible scope.

BACKGROUND: Interest in pure laparoscopic donor hepatectomy (PLDH) is increasing worldwide with the donor's cosmetic demands and improvements in surgical techniques. Efficient manipulation of flexible scope is mandatory for successful PLDH, especially in right hepatectomy which requires more mobilization. This study provides guidelines on how to manipulate optimally a flexible scope. METHODS: Data from 158 donors who underwent pure laparoscopic donor right hepatectomy (PLDRH) between November 2015 and December 2017 were retrospectively reviewed. RESULTS: None of the donors required transfusion, conversion to open hepatectomy, or experienced any irreversible disabilities or mortalities. Three types of laparoscopic view provided by the flexible scope, which are bird's eye view, low angle view, and lateral view, were applied to each step of the procedure. CONCLUSIONS: PLDRH can be successfully performed with maximizing visibility given by the tips and pitfalls in manipulating the flexible scope.

Delayed Repolarization Underlies Ventricular Arrhythmias in Rats With Heart Failure and Preserved Ejection Fraction.

BACKGROUND: Heart failure with preserved ejection fraction (HFpEF) represents approximately half of heart failure, and its incidence continues to increase. The leading cause of mortality in HFpEF is sudden death, but little is known about the underlying mechanisms. METHODS: Dahl salt-sensitive rats were fed a high-salt diet (8% NaCl) from 7 weeks of age to induce HFpEF (n=38). Rats fed a normal-salt diet (0.3% NaCl) served as controls (n=13). Echocardiograms were performed to assess systolic and diastolic function from 14 weeks of age. HFpEF-verified and control rats underwent programmed electrical stimulation. Corrected QT interval was measured by surface ECG. The mechanisms of ventricular arrhythmias (VA) were probed by optical mapping, whole-cell patch clamp to measure action potential duration and ionic currents, and quantitative polymerase chain reaction and Western blotting to investigate changes in ion channel expression. RESULTS: After 7 weeks of a high-salt diet, 31 of 38 rats showed diastolic dysfunction and preserved ejection fraction along with signs of heart failure and hence were diagnosed with HFpEF. Programmed electric stimulation demonstrated increased susceptibility to VA in HFpEF rats (P<0.001 versus controls). The arrhythmogenicity index was increased (P<0.001) and the corrected QT interval on ECG was prolonged (P<0.001) in HFpEF rats. Optical mapping of HFpEF hearts demonstrated prolonged action potentials (P<0.05) and multiple reentry circuits during induced VA. Single-cell recordings of cardiomyocytes isolated from HFpEF rats confirmed a delay of repolarization (P=0.001) and revealed downregulation of transient outward potassium current (Ito; P<0.05). The rapid components of the delayed rectifier potassium current (IKr) and the inward rectifier potassium current (IK1) were also downregulated (P<0.05), but the current densities were much lower than for Ito. In accordance with the reduction of Ito, both Kcnd3 transcript and Kv4.3 protein levels were decreased in HFpEF rat hearts. CONCLUSIONS: Susceptibility to VA was markedly increased in rats with HFpEF. Underlying abnormalities include QT prolongation, delayed repolarization from downregulation of potassium currents, and multiple reentry circuits during VA. Our findings are consistent with the hypothesis that potassium current downregulation leads to abnormal repolarization in HFpEF, which in turn predisposes to VA and sudden cardiac death.

Unusual Techniques for Preserving Surgical and Oncologic Safety in Hepatectomy of Advanced Adrenal Malignancy with Vena Cava and Liver Invasion.

BACKGROUND: Status in terms of major vascular structure invasion is a crucial factor for successful major hepatic resection. In particular, surgery for advanced tumors with inferior vena cava (IVC) invasion is difficult and may even be dangerous for the patient, having high risk of massive bleeding and greater chance of embolic complications such as stroke, bowel ischemia, and pulmonary venous thrombosis. For such reasons, many surgeons hesitate to carry out such surgical resection, and even if they do so, may not totally remove the tumor including the part inside the IVC, achieving R1 resection. For safe and radical surgery, various surgical techniques are required. We report herein three cases of major hepatectomy with IVC invasion and discuss several surgical tips. PATIENTS AND METHODS: From March 2011 to February 2014, we retrospectively reviewed three cases of adrenal malignancy with liver and IVC invasion. Based on the severity of the malignant tumor, each case illustrates a different method to address surgical complications and maintain oncologic safety. Case 1: A 34-year-old woman was diagnosed with adrenocortical tumor during medical examination. Tumor invaded the right lobe of the liver and very close to the IVC. Fortunately, there was little thrombosis inside the IVC; we performed right hemihepatectomy and adrenalectomy, then resected the IVC wall close to the tumor and repaired the IVC side wall using 4-0 Prolene. Case 2: A 54-year-old woman who complained of abdominal discomfort visited our hospital. Abdominal computed tomography (CT) scan revealed huge adrenal mass with liver and IVC invasion. Thrombosis inside the IVC extended to the right atrium. We decided to carry out veno-veno bypass during operation in collaboration with heart surgeon. After application of veno-veno bypass, the right atrium wall was opened and the tumor thrombus removed. We then carried out right hemihepatectomy and adrenalectomy. Supra- and infrahepatic vena cava were clamped during tumor thrombectomy to prevent embolic complications. Case 3: A 51-year-old woman who complained of headache and hypertension visited our hospital and was diagnosed with huge adrenal tumor. Tumor invaded to the right lobe of the liver and encased the IVC. The tumor totally invaded the IVC, and massive bleeding was expected during dissection. We resected the tumor including IVC en bloc, and reconstructed IVC with artificial graft (Dacron) under veno-veno bypass. RESULTS: In case 1, there was no surgical complication. The patient was discharged 7 days postoperatively and underwent adjuvant chemotherapy (Mitotane) after discharge. Unfortunately, multiple hepatic metastases were identified 4 months after operation. She died 6 months after surgery. In case 2, there was no surgical complication after surgery. The patient was discharged 10 days postoperatively. Multiple liver and lung metastases were identified 4 months after operation, and pulmonary embolism was also diagnosed on chemotherapy. She died 16 months after operation. In case 3, the patient had no surgical complication in the immediate postoperative period and was discharged 14 days after surgery. Pheochromocytoma was confirmed in pathologic report. One month after discharge, she underwent interventional balloon dilatation due to short segmental collapse of suprahepatic IVC. At 42 months after surgery, she was still alive with no relapse. DISCUSSION: In advanced-stage malignant tumor, the conflict between achieving oncologic R0 resection and patient safety remains an unsolved issue. In particular, more advanced surgical technique is required when the tumor invades large vessels such as the vena cava. Previous reports on cases of advanced tumor invading liver and IVC have described the technical difficulties.1,2 Wakayama et al. reported cases of successful thrombectomy under veno-veno bypass in hepatocellular carcinoma with IVC and right atrium invasion,3 and Vicente et al.4 reported surgical resection of IVC thrombus without cardiopulmonary bypass. Major vascular invasion of the tumor is known to be a poor prognostic factor for survival. However, some reports state that, if the tumor invades major vascular structure, complete tumor removal might be helpful for patient survival due to the biologic features of the tumor.2,5,6 This video report does not describe any new techniques, but is more helpful for junior surgeons in educational terms. The limitation of this report is that we could not show good oncologic long-term survival after surgery. However, no fatal complications related to the surgical procedure occurred, by managing the tumor thrombus during the operation. We present three techniques with differing aggressiveness. The techniques illustrated in this video represent a good option to achieve patient surgical safety.

Cardiac and systemic rejuvenation after cardiosphere-derived cell therapy in senescent rats.

AIM: The aim is to assess the effects of CDCs on heart structure, function, gene expression, and systemic parameters in aged rats. Diastolic dysfunction is characteristic of aged hearts. Cardiosphere-derived cell (CDC) therapy has exhibited several favourable effects on heart structure and function in humans and in preclinical models; however, the effects of CDCs on aging have not been evaluated. METHODS AND RESULTS: We compared intra-cardiac injections of neonatal rat CDCs to vehicle (phosphate-buffered saline, PBS) in 21.8 ± 1.6 month-old rats (mean ± standard deviation; n = 23 total). Ten rats 4.1 ± 1.5 months of age comprised a young reference group. Blood, echocardiographic, haemodynamic and treadmill stress tests were performed at baseline in all animals, and 1 month after treatment in old animals. Histology and the transcriptome were assessed after terminal phenotyping. For in vitro studies, human heart progenitors from older donors, or cardiomyocytes from aged rats were exposed to human CDCs or exosomes secreted by CDCs (CDC-XO) from paediatric donors. Transcriptomic analysis revealed that CDCs, but not PBS, recapitulated a youthful pattern of gene expression in the hearts of old animals (85.5% of genes differentially expressed, P < 0.05). Telomeres in heart cells were longer in CDC-transplanted animals (P < 0.0001 vs. PBS). Cardiosphere-derived cells attenuated hypertrophy by echo (P < 0.01); histology confirmed decreases in cardiomyocyte area (P < 0.0001) and myocardial fibrosis (P < 0.05) vs. PBS. Cardiosphere-derived cell injection improved diastolic dysfunction [lower E/A (P < 0.01), E/E' (P = 0.05), end-diastolic pressure-volume relationship (P < 0.05) compared with baseline), and lowered serum brain natriuretic peptide (both P < 0.05 vs. PBS). In CDC-transplanted old rats, exercise capacity increased ∼20% (P < 0.05 vs. baseline), body weight decreased ∼30% less (P = 0.05 vs. PBS) and hair regrowth after shaving was more robust (P < 0.05 vs. PBS). Serum biomarkers of inflammation (IL-10, IL-1b, and IL-6) improved in the CDC group (P < 0.05 for each, all vs. PBS). Young CDCs secrete exosomes which increase telomerase activity, elongate telomere length, and reduce the number of senescent human heart cells in culture. CONCLUSION: Young CDCs rejuvenate old animals as gauged by cardiac gene expression, heart function, exercise capacity, and systemic biomarkers.