Successful launch of robot-assisted mitral valve repair in Japan under universal health coverage.

OBJECTIVES: We compared the clinical outcomes of mitral valve repair for mitral regurgitation via the robot-assisted approach and small right thoracotomy approach 3 years after the reimbursement of the robot-assisted approach in Japan. METHODS: Patients who underwent isolated mitral valve repair by minimally invasive approach between 2018 and 2020 from the Japan Cardiovascular Surgery Database were included. Patients in the robot-assisted approach group were matched to the small right thoracotomy approach group based on propensity scores estimated from patient and surgical characteristics. Perioperative outcomes were compared among all cases as well as in subgroups categorized on the basis of the yearly number of robot-assisted approach cases and small right thoracotomy approach cases (≥10 or <10) at the hospital. RESULTS: We identified 2443 patients who had undergone isolated mitral valve repair at 250 institutions in the database, and analysis of propensity-matched 577 patient-pairs demonstrated that operation time, cardiopulmonary bypass time, and aortic crossclamp time were significantly shorter with the robot-assisted approach. Although the intensive care unit stay was longer in the robot-assisted approach, the time to discharge was significantly shorter in the robot-assisted approach. There was no meaningful difference in the in-hospital mortality. The incidences of postoperative stroke, renal failure, and prolonged ventilation, and the number of patients who converted to mitral valve replacement were similarly low. Procedural time, blood transfusions, explorative procedures for bleeding, postoperative stroke, and prolonged ventilation occurred at a lower rate in the high-volume institutions. CONCLUSIONS: The study found that the robot-assisted approach is just as effective as the small right thoracotomy approach. The introduction of robot-assisted mitral valve repair in Japan has been successful.

Sternal lifting technique for patients with sternal depression during robotic mitral repair.

INTRODUCTION: Traditional surgical methods have been difficult for patients with chest wall deformities, but the use of the Electrical Sternum Lifting System (ESLS) has made the surgery easier. MATERIALS AND SURGICAL TECHNIQUE: Patients with a sternum-to-vertebral distance of less than 80 mm on preoperative computed tomography (CT) scan routinely underwent sternal lift using the ESLS. The ESLS was effective in securing the operative field while suspending the sternum, allowing adequate observation of the left atrium, left ventricle, and the mitral valve, and safe mitral valve plasty. The use of the lifting device did not interfere with the robot arms, and the space between the sternum and vertebrae was widened with only a 3 mm wound to move the mitral valve surface in the sagittal plane, making the repair easy and accurate under robotic assistance. The effort to attach the ESLS was not difficult, and the postoperative cosmetic outcomes were excellent. Sixty-three out of 1002 patients (6.3%) underwent sternal elevation using ESLS. There were 19 males and 44 females with a mean age of 50.9 ± 14.0 years. The average of sternum-to-vertebral (S/V) distance was 72.4 ± 8.9 cm. Two patients had S/V distance of more than 80 mm but ESLS was used because of scoliosis.

Triplet dynamic nuclear polarization of pyruvate via supramolecular chemistry.

Dynamic nuclear polarization (DNP) significantly improves the sensitivity of magnetic resonance imaging, and its most important medical application is cancer diagnosis via hyperpolarized 13C-labeled pyruvate. Unlike cryogenic DNP, triplet-DNP uses photoexcited triplet electrons under mild conditions. However, triplet-DNP of pyruvate has not been observed because of incompatibility of the hydrophobic polarizing agent with hydrophilic pyruvate. This work demonstrates that supramolecular complexation with ß-cyclodextrin can disperse 4,4'-(pentacene-6,13-diyl)dibenzoate (NaPDBA), a pentacene derivative with hydrophilic substituents, even in the presence of high sodium pyruvate concentrations. The polarization of photoexcited triplet electron spins in NaPDBA was transferred to the 13C spins of sodium pyruvate via triplet-DNP of 1H spins in water and 1H-to-13C cross-polarization. This provides an important step toward the widespread use of ultra-sensitive MRI for cancer diagnosis.

Outcomes of Barlow mitral valve repaired by robot-assisted keyhole surgery.

Objective: To present our strategy and the clinical outcomes of robot-assisted Barlow mitral valve keyhole surgery. Methods: From May 2015 to March 2022, a total of 1281 patients underwent mitral valve repair at our institution, including 763 with robotics surgeries. Of these, 124 patients with Barlow mitral valve (49 ± 12 years, male/female ratio = 81:43) were treated using robotic assistance and included in this study. Results: All operations were completed using 3 to 5 keyholes. Neochordae implantation using the loop technique was the first option, and resection was performed only in cases with an intrinsic risk of developing systolic anterior motion. Neochordae implantation was performed in 118 cases (95.1%) using 6.6 ± 3.0 neochordae. Posterior leaflet resection was performed in 27 (21.7%) patients. Operation time was 177 ± 42 minutes, cardiopulmonary bypass time was 127 ± 25 minutes, and aorta crossclamp time was 76 ± 16 minutes. Blood transfusion was required in 5 cases (4%). None of the patients required a conversion to valve replacement. The postoperative complications included bleeding (n = 4), stroke (n = 1), and infection (n = 2). Mitral valve regurgitation 1 week after repair was none or trivial in 122 cases (98.3%), mild in 2 cases (1.7%), and more than moderate in 0 cases. Freedom from reoperation was 99.2% during the follow-up period of 36 ± 21 months. One patient required reoperation due to infective endocarditis. Conclusions: Robot-assisted keyhole surgery using the loop-first concept was adequate to help achieve satisfactory and safe perioperative outcomes for Barlow mitral valve.

Robotic Surgery for Triple Valve Insufficiency: A Case Report.

A 63-year-old woman was referred to our institution for surgical treatment of triple valve (aortic, mitral, and tricuspid) insufficiency and underwent a robot-assisted endoscopic procedure. Three intercostal ports were placed in the right lateral chest for robotic instruments and a retrograde cardioplegic cannula, and a 5 cm thoracotomy was made for the procedure, which was a mitral valve repair with neochords and ring annuloplasty, an aortic valve replacement with bioprosthetic valve, and a ring tricuspid annuloplasty. Surgery was successfully achieved without blood transfusion or any complications.

Off-Pump Neochordae Implantation via Left Minithoracotomy for Recurrent Regurgitation Following Mitral Valve Repair: The First Case in Japan.

Surgical fixation after recurrent regurgitation following surgical mitral repair has been technically demanding and associated with high morbidity and mortality. Avoiding reopening the adhesive site or limiting the usage of cardiopulmonary bypass are solutions for reducing the operative risk. We report a case of recurrent mitral regurgitation treated by off-pump neochordae implantation via left minithoracotomy. A 69-year-old woman with a history of conventional mitral repair via median sternotomy developed heart failure due to mitral regurgitation from recurrent posterior leaflet P2 prolapse. Four neochordaes were implanted off-pump via left minithoracotomy using a NeoChord DS1000 in the seventh intercostal space. No transfusion was required. The patient was discharged a week after the procedure with no complications. The regurgitation remains trivial 6 months after the NeoChord procedure.

Effects of Lenvatinib on Skeletal Muscle Volume and Cardiac Function in Patients with Hepatocellular Carcinoma.

INTRODUCTION: Previously, we reported that the tyrosine kinase inhibitor (TKI) sorafenib decreases serum levels of carnitine and reduces skeletal muscle volume. Moreover, others reported that TKIs might lead to cardiomyopathy or heart failure. Therefore, this study aimed to evaluate the effects of lenvatinib (LEN) on skeletal muscle volume and cardiac function in patients with hepatocellular carcinoma (HCC). METHODS: This retrospective study included 58 adult Japanese patients with chronic liver diseases and HCC treated with LEN. Blood samples were collected before and after 4 weeks of treatment, and serum carnitine fraction and myostatin levels were measured. Before and after 4-6 weeks of treatment, the skeletal muscle index (SMI) was evaluated from computed tomography images and cardiac function was assessed by ultrasound cardiography. RESULTS: After treatment, SMI, serum levels of total carnitine, and global longitudinal strain were significantly lower, but serum levels of myostatin were significantly higher. Left ventricular ejection fraction showed no significant change. CONCLUSION: In patients with HCC, LEN decreases serum levels of carnitine, skeletal muscle volume, and worsens cardiac function.

Tumor-derived semaphorin 4A improves PD-1-blocking antibody efficacy by enhancing CD8+ T cell cytotoxicity and proliferation.

Immune checkpoint inhibitors (ICIs) have caused revolutionary changes in cancer treatment, but low response rates remain a challenge. Semaphorin 4A (Sema4A) modulates the immune system through multiple mechanisms in mice, although the role of human Sema4A in the tumor microenvironment remains unclear. This study demonstrates that histologically Sema4A-positive non-small cell lung cancer (NSCLC) responded significantly better to anti-programmed cell death 1 (PD-1) antibody than Sema4A-negative NSCLC. Intriguingly, SEMA4A expression in human NSCLC was mainly derived from tumor cells and was associated with T cell activation. Sema4A promoted cytotoxicity and proliferation of tumor-specific CD8+ T cells without terminal exhaustion by enhancing mammalian target of rapamycin complex 1 and polyamine synthesis, which led to improved efficacy of PD-1 inhibitors in murine models. Improved T cell activation by recombinant Sema4A was also confirmed using isolated tumor-infiltrating T cells from patients with cancer. Thus, Sema4A might be a promising therapeutic target and biomarker for predicting and promoting ICI efficacy.

Robot-Assisted Totally Endoscopic Mitral Valve Plasty and Coronary Artery Bypass Grafting.

We experienced 3 cases of port-access robot-assisted totally endoscopic technique for mitral valve repair and concomitant coronary artery bypass. The right internal mammary artery was harvested, mitral valve was fixed, and the right internal mammary artery to right coronary artery anastomosis was carried out on the arrested heart. The use of cardiac arrest and a V-shaped hook technique facilitated the coronary anastomosis and the da Vinci Firefly test (Intuitive Surgical Inc., Sunnyvale, CA) could confirm patency of the graft.

A routine de-airing method for total endoscopic robot-assisted mitral valve repair.

Intraoperative water testing is essential for assessing mitral valve morphology and degree of residual mitral regurgitation during mitral valve repair. However, in some cases, evacuating intracardiac air is challenging. Herein, we report the routine de-airing method during total endoscopic robot-assisted mitral valve repair at our institute and discuss its effectiveness. In brief, our de-airing methods involve the following steps: after restricting the blood flow of the cardiopulmonary bypass, intracardiac air was pushed out into the pulmonary veins by drawing blood from the right ventricle. The left atrium, left ventricle, and ascending aorta were filled with blood to remove air from the root cannula. Retrograde blood flow from the coronary sinus was used to remove air from the coronary arteries. At 10 min after cardiopulmonary bypass weaning, transesophageal echocardiography revealed that residual intracardial air was absent in 99% of patients in all three chambers (ascending aorta, left atrium, and left ventricle).

Lenvatinib Might Induce Activation of Host Immunity in Patients with Hepatocellular Carcinoma.

INTRODUCTION: Atezolizumab, an immune checkpoint inhibitor, plus bevacizumab, a monoclonal antibody that binds to vascular endothelial growth factor (VEGF), is an approved first-line systemic treatment for unresectable hepatocellular carcinoma (HCC). Immune checkpoint inhibitors are more effective in patients with HCC when administered with anti-VEGF drugs; however, these drugs affect host immunity. Lenvatinib is an anti-VEGF agent used to treat HCC; therefore, this study evaluated the effect of treatment of HCC with lenvatinib on host immunity in patients with chronic liver disease (CLD). METHODS: We studied adult Japanese patients with CLD and unresectable HCC treated with lenvatinib at our hospital. Lenvatinib was administered for 4 weeks (8 mg/day for bodyweight <60 kg; 12 mg/day for bodyweight >60 kg). Blood samples were collected at baseline and at 4 weeks of treatment and examined for immune-related changes. RESULTS: Forty-three patients were enrolled in this study. We found a significant increase in T helper (Th) 1 cells following 4 weeks of lenvatinib treatment, although there was no significant difference in Th2 cells and regulatory T cells. We also found a significant increase in serum levels of TNF-alpha, soluble TNF-alpha receptor I, and endothelial growth factor following 4 weeks of lenvatinib treatment. Furthermore, an increase in Th1 cells and serum levels of TNF-alpha was found in patients with partial response. CONCLUSION: Lenvatinib might induce Th1-dominant host immunity in patients with CLD and unresectable HCC treatment in patients who showed a partial response. These changes in host immunity may be a biomarker in HCC patients treated with lenvatinib.

[Robot-assisted Cardiac Surgery Council and Current Status and Future Prospect of Robotic Mitral Valve Surgery in Japan].

The Robot-assisted Cardiac Surgery Council (RACSC) was established in 2015, and consists of the members of three closely related surgical societies and associations. The RACSC conducts the review and approval of applicant surgeons and institutions. A registry system has also been established through the Japan Cardiovascular Surgery Database-National Clinical Database( JCVSD-NCD). For the last five years, including the time when robotic mitral valve surgery was first approved as a procedure covered by the Japanese social insurance system in 2018, a total of 1,161 patients were enrolled in the JCVSDNCD, with an increase of nearly 500 cases per year. These cases underwent operations in 25 approved hospitals. The mean patient age was 59±13 years( range:20-90 years), and the male to female patient ratio was 1.8 male dominant. The most common procedure was mitral valve reconstruction, and 79% of all patients underwent annuloplasty. The mean operative time was 238±100 min, the mean cardiopulmonary bypass (CPB) time was 158±69 min, and the mean aortic cross-clamp (AXC) time was 102±49 min. When these results were compared with those of the Cleveland Clinic, which treated more than 1,000 cases as an initial institutional experience, both CPB and AXC times were nearly the same. It is believed that 200 cases are needed to stabilize the CPB and AXC time. Currently in Japan, only 3 or 4 out of the 25 approved hospitals have performed more than 200 cases over the past 5 years. The 30-day hospital mortality and redo operation rate for persisting mitral regurgitation was 0.3% and 0.6%, respectively, almost equivalent to that of the Cleveland Clinic. We believe that the 5-year result for robotic mitral surgery in Japan is acceptable. It is of note, however, that the length of hospital stay was 10.8±7.6 days, much longer than that of patients at the Cleveland Clinic( 5.2±2.8 days), and the homologous blood transfusion rate was 40.3%, twofold higher than that of the Cleveland Clinic( 20.5%). Therefore, the full benefits of less invasive robotic mitral repair surgery have not yet been achieved. Further improvements in results are both essential and anticipated.

[Current Status of Robot-assisted Cardiac Surgery in Japan].

Endoscopic surgery has been introduced as a minimally invasive procedure in other fields. On the other hand, the introduction of surgical robots has made endoscopic surgery possible in cardiac surgery. Coronary artery bypass surgery includes minimally invasive direct coronary artery bypass( MIDCAB) via small thoracotomy after robotic internal thoracic artery harvesting and totally endoscopic coronary artery bypass with a robotic anastomosis. We refer to intracardiac surgery performed via only ports as "keyhole cardiac surgery". Robotic keyhole mitral valve repair is far superior to median sternotomy or minimally invasive cardiac surgery( MICS). Currently, the "da Vinci surgical system" is the sole leader in surgical robotics, but there are already many surgical robots, including new concepts. In Japan, the "hinotori surgical robot system" is already on the market, and it is expected that the indications for surgery will expand in the future.

Robotic mitral valve plasty for isolated clefts of mitral valve leaflets.

A 21-year-old female patient referred to our institute had been suffering from severe mitral valve regurgitation due to a rare anomaly: a typical cleft at the posterior mitral leaflet and the other partial one at the anterior leaflet. We successfully fixed the mitral valve using the robot-assisted totally endoscopic technique which could perform suture closure of both leaflets and annuloplasty. This communication is the first report of the robotic and totally endoscopic procedure which could treat this rare mitral anomaly.

Lactic acid promotes PD-1 expression in regulatory T cells in highly glycolytic tumor microenvironments.

The balance of programmed death-1 (PD-1)-expressing CD8+ T cells and regulatory T (Treg) cells in the tumor microenvironment (TME) determines the clinical efficacy of PD-1 blockade therapy through the competition of their reactivation. However, factors that determine this balance remain unknown. Here, we show that Treg cells gain higher PD-1 expression than effector T cells in highly glycolytic tumors, including MYC-amplified tumors and liver tumors. Under low-glucose environments via glucose consumption by tumor cells, Treg cells actively absorbed lactic acid (LA) through monocarboxylate transporter 1 (MCT1), promoting NFAT1 translocation into the nucleus, thereby enhancing the expression of PD-1, whereas PD-1 expression by effector T cells was dampened. PD-1 blockade invigorated the PD-1-expressing Treg cells, resulting in treatment failure. We propose that LA in the highly glycolytic TME is an active checkpoint for the function of Treg cells in the TME via upregulation of PD-1 expression.

Adaptation of lenvatinib treatment in patients with hepatocellular carcinoma and portal vein tumor thrombosis.

PURPOSE: The aim of this study was to clarify the adaptation of lenvatinib treatment in patients with hepatocellular carcinoma (HCC) and portal vein tumor thrombosis (PVTT). METHOD: Fifty-three patients with HCC were treated with lenvatinib. Before and after treatment blood sampling, patients were examined by computed tomography and ultrasonography. In patients with portal trunk invasion (Vp4), the analysis focused on the degree of occlusion due to the tumor in the portal trunk. In patients without major PVTT {ie, invasion of the primary branch of the portal vein [Vp3] or Vp4}, portal blood flow volume was measured by Doppler analysis; however, Doppler analysis is difficult to perform in patients with major PVTT, so the time from administration of the contrast agent to when it reached the primary branch of the portal vein (portal vein arrival time) was evaluated with the contrast agent Sonazoid. RESULTS: Patients with Vp4 had a significantly worse prognosis than patients with Vp3 and a significant increase in Child-Pugh score at 2 months. Patients with major PVTT had a poor prognosis if the degree of occlusion of the portal trunk was 70% or more. In patients without major PVTT, portal blood flow was significantly decreased after administration of lenvatinib; and in patients with major PVTT, the hepatic artery and portal vein arrival times were significantly increased. CONCLUSION: Lenvatinib treatment should be avoided in patients with Vp4 with a high degree of portal trunk occlusion because of concerns about decreased portal blood flow.

Bilateral endoscopic technique for left atrial appendectomy and robot-assisted mitral valve repair.

We report a bilateral thoracoscopic technique in which robot-assisted mitral valve repair was achieved concomitantly with stapler division of the large left atrial appendage. The patient was a 65-year-old male with severe mitral regurgitation, paroxysmal atrial fibrillation and a large-sized atrial appendage. Closure of the appendage was completed off-pump using a left thoracoscopic stapler-division technique previous to right thoracoscopic robot-assisted mitral valve repair and cryoablation. Complete closure of the appendage was confirmed in thoracoscopic views. The bilateral thoracoscopic technique could be preferable for the minimally invasive treatment of mitral valvular disease and concomitant large-sized atrial appendage management.

Efficient protein incorporation and release by a jigsaw-shaped self-assembling peptide hydrogel for injured brain regeneration.

During injured tissue regeneration, the extracellular matrix plays a key role in controlling and coordinating various cellular events by binding and releasing secreted proteins in addition to promoting cell adhesion. Herein, we develop a cell-adhesive fiber-forming peptide that mimics the jigsaw-shaped hydrophobic surface in the dovetail-packing motif of glycophorin A as an artificial extracellular matrix for regenerative therapy. We show that the jigsaw-shaped self-assembling peptide forms several-micrometer-long supramolecular nanofibers through a helix-to-strand transition to afford a hydrogel under physiological conditions and disperses homogeneously in the hydrogel. The molecular- and macro-scale supramolecular properties of the jigsaw-shaped self-assembling peptide hydrogel allow efficient incorporation and sustained release of vascular endothelial growth factor, and demonstrate cell transplantation-free regenerative therapeutic effects in a subacute-chronic phase mouse stroke model. This research highlights a therapeutic strategy for injured tissue regeneration using the jigsaw-shaped self-assembling peptide supramolecular hydrogel.

Safety of perioperative period in robot-assisted atrial septal defect repair under hyperkalemic arrest.

BACKGROUND: Various attempts have been made to meet patient desires, especially among younger and otherwise healthy individuals, for cosmetically satisfying incision with atrial septal defect (ASD) repair. One of procedures was a robotic-assisted totally endoscopic ASD repair via only two ports under hyperkalemic arrest without aortic cross-clamping. This study investigated perioperative management and safety for robotic-assisted total endoscopic ASD repair surgery under hyperkalemic arrest. METHODS: We retrospectively reviewed perioperative management of thirty patients who underwent total endoscopic robot-assisted ASD repair under hyperkalemic arrest. All procedures were performed under general anesthesia using robotic-assisted total endoscopic for ASD repair via two or three ports under hyperkalemic arrest without aortic cross-clamping. RESULTS: A total of 30 patients (mean age 45 ± 17 years, 8 male, 22 female) underwent successful ASD repair with the total endoscopic robotic-assisted procedures under hyperkalemic arrest. Hyperkalemic arrest was achieved and maintained by intravenous administration of mean potassium dose of 91±32 mEq (1.4±0.6 mEq/kg) with the lowest bladder temperature was 31.9±1.4 °C during hyperkalemic arrest. In all cases, serum potassium concentration was <5.0 mEq/L after weaning from cardiopulmonary bypass, although two cases who developed hyperkalemia >6 mEq/L after operation. At other time points, no patient exceeded 6 mEq/L of serum potassium concentration. At admission to the intensive care unit, mean serum creatine phosphokinase-MB level was 32±7mg/dL. There were no cases of arrhythmia or other cardiac complications during recovery. CONCLUSIONS: Perioperative management of robotic-assisted total endoscopic ASD repair under hyperkalemic arrest is safe and is not associated with fatal arrhythmia due to hyperkalemia.