Impact of non-driver gene mutations on thrombo-haemorrhagic events in ET patients.

Risk-adapted therapy is recommended to prevent major clinical complications, such as thrombo-haemorrhagic events, in patients with essential thrombocythaemia (ET). In this study, we analysed the association between non-driver gene mutations and thrombo-haemorrhagic events in 579 patients with ET. ASXL1 and TP53 mutations were frequently identified in patients with ET complicated by thrombosis (22.7% and 23.1%, respectively), and the DNMT3A mutation was frequently identified in patients who experienced haemorrhage (15.2%). Multivariate analyses of thrombosis-free survival (TFS) revealed that ASXL1 and TP53 mutations are associated with thrombosis (hazard ratio [HR] = 3.140 and 3.752 respectively). Patients harbouring the ASXL1 or TP53 mutation had significantly worse TFS rates than those without mutation (p = 0.002 and p < 0.001 respectively). Furthermore, JAK2V617F-mutated patients with accompanying ASXL1 mutations showed significantly shorter TFS compared with those without ASXL1 mutations (p = 0.003). Multivariate analyses of haemorrhage-free survival (HFS) revealed that the DNMT3A mutation (HR = 2.784) is associated with haemorrhage. DNMT3A-mutated patients showed significantly shorter HFS than those without the mutation (p = 0.026). Non-driver gene mutations should be considered in treatment strategies and may provide important information for personalised treatment approaches.

Clinical Prognosis of Vocal Cord Paralysis After Cardiothoracic Surgery in Infants.

We aimed to clarify the long-term outcomes and prognosis of vocal cord paralysis (VCP) after cardiothoracic surgery in infants as well as the usefulness of laryngeal ultrasound (LUS) as screening for VCP. Overall, 967 infants aged 1-year-old or younger who underwent cardiothoracic surgery between 2008 and 2022 were included in this study. We divided the patients into two groups based on the period on whether they underwent screening without or with LUS and compared the incidence of VCP between the groups. There were no differences in the patients' preoperative characteristics between the two periods, whereas the incidence of VCP was significantly higher in period 2 than in period 1 (11.0% vs. 3.2%, p < 0.0001). The incidence of VCP among the procedures, including aortic arch repair, was > 50% and significantly increased from period 1 to period 2. The sensitivity and specificity of LUS was 87% and 90%, respectively. Symptoms of VCP improved in 92% of patients. Repeated flexible laryngoscopy revealed that the residual rate of VCP was 68%, 52%, and 48% at 6, 12, and 24 months, respectively. In conclusion, symptoms of postoperative VCP improved in most cases; however, paralysis persisted in half of the patients. As a screening method, LUS is useful for evaluating postoperative VCP. A more accurate understanding of VCP is needed to improve postoperative outcomes.

Non-driver gene mutation analysis in a large cohort of polycythemia vera and essential thrombocythemia.

OBJECTIVES: A proportion of patients with polycythemia vera (PV) and essential thrombocythemia (ET) harbor non-driver mutations associated with poor prognosis. In this study, we analyzed the frequency of non-driver mutations in a large Japanese PV and ET cohort. Furthermore, we studied the relationship of these mutations and prognosis in Japanese patients. METHODS: We enrolled 843 Japanese patients with PV or ET. Non-driver mutations were analyzed by target resequencing using next-generation sequencing. The association of the mutations with the prognosis was estimated using multivariable logistic regression analysis and log-rank test. RESULTS: Non-driver mutations were detected in 31.1% and 24.5% patients with PV and ET, respectively. Among them, ASXL1 mutations were identified as a risk factor for leukemic/myelofibrotic transformation in PV and ET patients (hazard ratio: 4.68, p = .006). The higher-risk groups of the mutation-enhanced international prognostic system (MIPSS)-PV and MIPSS-ET incorporating non-driver mutations exhibited significantly shorter overall survival compared with the low-risk group (p < .001). CONCLUSIONS: These results implicate the importance of studying non-driver mutations for predicting the prognosis and survival of Japanese PV and ET patients.

Reevaluation of cardiovascular risk factors for thrombotic events in 580 Japanese patients with essential thrombocythemia.

Risk-adapted therapy is recommended to prevent thrombosis in essential thrombocythemia (ET) patients. An advanced age, a history of thrombosis, and the presence of the JAK2V617F mutation are well-defined risk factors for thrombosis in ET; however, the impact of cardiovascular risk (CVR) factors on thrombosis in ET remains elusive. Therefore, we herein investigated the impact of CVR factors on thrombosis in 580 ET patients who met the 2017 World Health Organization Classification diagnostic criteria. A univariate analysis identified hypertriglyceridemia and multiple CVR factors as strong risk factors for thrombosis (hazard ratio [HR] 3.530, 95% confidence interval [CI] 1.630-7.643, P = 0.001 and HR 3.368, 95% CI 1.284-8.833, P = 0.014, respectively) and hyper-LDL cholesterolemia as a potential risk factor (HR 2.191, 95% CI 0.966-4.971, P = 0.061). A multivariate analysis revealed that hypertriglyceridemia was an independent risk factor for thrombosis (HR 3.364, 95% CI 1.541-7.346, P = 0.002). Furthermore, poor thrombosis-free survival was observed in patients with a serum triglyceride level ≥ 1.2 mmol/L (HR = 2.592, P = 0.026 vs. < 1.2 mmol/L) or two or more CVR factors (P = 0.011 vs. no CVR factors and P = 0.005 vs. one CVR factor). These results revealed the impact of CVR factors on thrombosis in ET. Since CVR factors are manageable, lifestyle interventions, such as the control of serum triglyceride levels, may effectively prevent thrombosis in ET patients.

von Willebrand factor activity levels are influenced by driver mutation status in polycythemia vera and essential thrombocythemia patients with well-controlled platelet counts.

von Willebrand factor ristocetin cofactor (vWF activity) and platelet count (PLT) are negatively correlated in patients with polycythemia vera (PV) and essential thrombocythemia (ET). However, vWF activity does not always normalize upon controlling PLT in those patients. To address this issue, we investigated the correlation between vWF activity and PLT in PV and ET patients. The negative correlation between vWF activity and PLT was stronger in calreticulin mutation-positive (CALR+) ET than in Janus kinase 2 mutation-positive (JAK2+) PV or ET groups. When PLT were maintained at a certain level (<600 × 109 /L), low vWF activity (<50%) was more frequently observed in JAK2+ PV patients than in JAK2+ ET (p = .013) or CALR+ ET (p = .013) groups, and in PV and ET patients with ≥50% JAK2+ allele burden than in those with allele burden <50% (p = .015). High vWF activity (>150%) was more frequent in the JAK2+ ET group than in the CALR+ ET group (p = .005), and often associated with vasomotor symptoms (p = .002). This study suggests that some patients with JAK2+ PV or ET have vWF activity outside the standard range even with well-controlled PLT, and that the measurement of vWF activity is useful for assessing the risk of thrombosis and hemorrhage.

Endovascular Repair for Abdominal Aortic Aneurysm Rupture With Neurofibromatosis Type 1.

BACKGROUND: Neurofibromatosis type 1 (NF1), also known as von Recklinghausen disease, is a rare congenital disorder with an autosomal dominant inheritance. Severe perioperative complications owing to the congenital fragility of the vascular wall in NF1 patients have been reported. The optimal vascular surgical approach remains controversial. We describe endovascular aortic repair of an abdominal aortic aneurysm rupture in a patient with NF1. CASE PRESENTATION: A 78-year-old woman with NF1 was transferred to our institution with a diagnosis of ruptured abdominal aortic aneurysm. The patient showed multiple café-au-lait spots, numerous neurofibromatosis, and severe scoliosis. Emergency endovascular aortic repair was performed, without technical difficulty. Despite an uneventful postoperative course, she developed an idiopathic left cervical hematoma caused by hemorrhage, and required tracheostomy due to severe airway obstruction. In addition, postoperative CT showed a newly developed saccular aneurysm at the proximal end of the stent graft. On postoperative day 40, she was transferred to a rehabilitation hospital, without recurrent bleeding and saccular aneurysm enlargement. CONCLUSION: In patients with NF1 who require a vascular surgical procedure, surgeons should consider the vascular wall fragility in selecting the optimal treatment strategy and the possible complications.

[Successful Surgical Repair for Adult Ebstein Disease Using Cone Reconstruction Combined with One and a Half Ventricle Repair].

A 67-year-old woman presented with dyspnea on effort and cyanosis due to massive tricuspid regurgitation and an atrial septal defect with right to left shunt. She was diagnosed with Ebstein disease at the age of 53 when she underwent surgery for varicose veins. Echocardiography showed the severe apical displacement of the septal and posterior leaflet. The anterior leaflet also partially displaced to the apex and demonstrated tethering caused by a dilated right ventricle. Cardiac magnetic resonance imaging showed a dilated right atrium and an enlarged atrialized right ventricle, in addition to marked low cardiac output in the dilated right ventricle. The surgical findings corresponded to Carpentier classification type C. Cone reconstruction was performed. Bidirectional Glenn anastomosis was reguired because of low cardiac output in the remaining functional right ventricle after Cone reconstruction. The patient's postoperative course was uneventful, and tricuspid regurgitation and stenosis remained mild. The patients had no occurrence of right heart failure or arrhythmia for two years after surgery.

[Successful Surgical Repair of Left Coronary Ostial Aneurysm after Modified Bentall Procedure Using the Carrel Patch Technique].

A 38-year-old woman underwent aortic root surgery using the Carrel patch technique at the age of 14 years for annuloaortic ectasia of 59 mm. Although there were no clinical findings of Marfan syndrome or bicuspid aortic valve, the pathological findings of the aortic aneurysmal wall showed degeneration of the media. After 24 years, contrast-enhanced computed tomography (CT) showed an enlargement of the left coronary ostial aneurysm of 17 mm with saccular formation. Re-coronary reconstruction with the Piehler technique using an 8 mm Dacron graft was performed. The post-operative course was uneventful, and post-operative CT showed no pseudoaneurysm or stenosis at the anastomosis sites. The Carrel patch coronary ostial reconstruction has been shown to reduce coronary anastomotic pseudoaneurysms and to improve aortic root surgical outcomes. However, coronary ostial aneurysm is a true aneurysm and one of the later complications after the modified Bentall procedure using the Carrel patch technique. Although it is common in Marfan syndrome, the consensus on diagnosis, operative indication, and surgical procedure have not yet been established. Not only in Marfan syndrome, but also after coronary artery reconstruction using the Carrel patch technique, longer-term follow-up is necessary to take care for aneurysmal formation at coronary ostium.

[Aortic Root Replacement with Patch Closure of Membranous Ventricular Septal Aneurysm].

Membranous ventricular septal aneurysm (MSA) complicated with annuloaortic ectasia (AAE) is rare in adults. Herein, we reported two successful surgical cases of this setting. One case is 50-year-old man with extensive infective endocarditis with underwent aortic coarctation repair in childhood. MSA was incidentally diagnosed at preoperative examination. The other patient is 53-year-old man who had severe aortic regurgitation complicated with AAE and membranous type ventricular septal defect with MSA. Simultaneous surgery comprising patch closure of MSA and aortic root replacement was performed in both patients. As for patch closure of MSA, the technical modification should be necessitated according to the fragility of the upper margin of the MSA.

Step-by-step aortic clamping technique for safe retrieval of the elephant trunk.

Staged repair of the aortic arch and downstream aorta using the elephant trunk technique is widely accepted for extensive aortic disease. However, elephant trunk retrieval is challenging in patients with unclampable descending aorta caused by extreme aneurysmal dilation or surrounding tissue adhesion. Here, we introduce a new elephant trunk retrieval technique using the step-by-step aortic clamping in descending aortic replacement of dissecting aortic aneurysm. This technique is a safe and feasible method of elephant trunk retrieval that consists of staged clamping and intraoperative ultrasound assessment of blood flow in the aorta.

Simple Retrieval Technique of the Elephant Trunk by Partial Aortic Clamping.

The frozen elephant trunk technique for various thoracic aortic diseases is widely accepted to facilitate future downstream aortic surgery. However, in some cases, the descending aorta is unsuitable for cross-clamping due to progressive aneurysmal changes or dense adhesions to surrounding structures, and frozen elephant trunk retrieval becomes challenging. This paper presents a case of successful frozen elephant trunk retrieval by partial clamping of the descending aortic aneurysm without dissection of peri-aneurysmal adhesions, and subsequent encircling.

[Immune thrombocytopenia preceded by asymptomatic COVID-19 infection].

Immune thrombocytopenia (ITP) may occur following a viral infection. We report the case of a 30-year-old woman with thrombocytopenia who was subsequently diagnosed with ITP. Although she was asymptomatic, chest computed tomography (CT) showed ground-glass opacities in the lower lung regions. The patient had a positive severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) real-time polymerase chain reaction (RT-PCR) test. She responded well to 400 mg/kg of intravenous immunoglobulin therapy. Coronavirus disease of 2019 or COVID-19 should be considered as a cause of ITP during the pandemic, and chest CT scans and RT-PCR tests should be performed in patients suspected of ITP.

[Total Arch Replacement with Brain Isolation Technique for Arch Aneurysm with Shaggy Aorta].

A shaggy aorta with a mobile atheromatous plaque in a thoracic lesion is considered a risk factor for cerebral infarction during aortic arch surgery. The brain isolation technique was introduced to prevent embolic stroke either by manipulating the severely atheromatous aorta, or by producing a sandblasting effect using the arterial jet in cardiopulmonary bypass. We performed total arch replacement with the aid of a brain isolation technique in four patients with aortic arch aneurysm complicated with a shaggy aorta between 2016 and 2020. Antegrade selective cerebral perfusion was established prior to systemic perfusion of the cardiopulmonary bypass. Total arch replacement using the frozen elephant technique was performed in all patients. There was no operative mortality, and all patients were discharged without major neurological complications. Therefore, the brain isolation technique could be a useful adjunctive method to prevent embolic stroke in patients who undergo total arch replacement for aortic arch aneurysm with a shaggy aorta.

[Surgical Strategy for Aortic Arch Aneurysms in Octogenarians].

BACKGROUNDS: The purpose of this study was to evaluate the short- and mid-term outcomes of open aortic arch surgery and debranching thoracic endovascular aortic repair( TEVAR) in octogenarians. METHODS: Between 2011 and 2019, 26 patients with atherosclerotic aortic arch aneurysms underwent surgery at our institution [open aortic arch surgery( group O):10 patients, debranching TEVAR(group D):16 patients]. RESULTS: There was no operative death in either group. The mean length of hospitalization and intensive care unit stay were 49 and 13 days in group O and 12 and 2 days in group O, respectively. Kaplan-Meier analyses of overall survival (1/6/12/24/36/48 months) showed mortality rates of 100/100/88/88/70/70% in group O and 100/100/87/61/43/26% in group D, respectively. CONCLUSIONS: The acceptable outcomes was demonstrated in octogenarians underwent both open aortic arch surgery and debranching TEVAR. Because of early postoperative recovery, debranching TEVER is considered to be a feasible alternative to conventional open aortic arch surgery in octogenarians.

Ruptured aneurysm of coronary arteriovenous fistula without aneurysmal coronary artery.

BACKGROUND: Approximately 25% of coronary arteriovenous fistulas present aneurysmal dilatation; however, spontaneous rupture of the aneurysm is rare. Most coronary arteries branching the feeding arteries demonstrate aneurysmal formation, possibly because of shunt flow. CASE REPORT: A 48-year-old woman was referred to our institution for surgical management of ruptured aneurysm of coronary arteriovenous fistula. The aneurysm was located on the left-anterior aspect of the pulmonary artery trunk, communicating with both left and right coronary arteries through two small feeding arteries draining into the pulmonary artery trunk. Both left and right coronary arteries showed normal diameter. The feeding arteries were ligated externally, and fistulous openings were closed within the aneurysm. Postoperative course was uneventful. CONCLUSION: Aneurysm of coronary arteriovenous fistula can occur in patients without aneurysmal coronary artery. Although the association of ruptured aneurysm with coronary fistulas is relatively rare, it should be considered a potential cause of acute cardiac tamponade.

Surgical treatment for saphenous vein graft aneurysm without redo sternotomy.

BACKGROUND: Saphenous vein graft aneurysm (SVGA) is a rare complication after coronary artery bypass grafting; however, it may lead to fatal conditions. A redo sternotomy poses a high risk of injury to the patent graft. CASE REPORT: A 59-year-old man with chest pain was diagnosed with a giant SVGA (67 mm) anastomosed to the right coronary artery (RCA) and compressing the right atrium. Considering the high risk of injury to a patent graft through the sternum, a surgical procedure was planned without redo sternotomy. Through an upper midline abdominal incision, redo bypass grafting was performed to the distal RCA using the right gastroepiploic artery, followed by resection of the aneurysm using the right anterior lateral thoracotomy approach. The postoperative course was uneventful. CONCLUSION: In patients with an SVGA anastomosed to the right coronary system, our surgical strategy may be a useful alternative to redo sternotomy to avoid injury to the patent graft.

[Microgranular-type acute promyelocytic leukemia with weak myeloperoxidase staining: difficulty of morphological diagnosis].

The 2017 World Health Organization (WHO) classification states that acute promyelocytic leukemia (APL) always presents with strong myeloperoxidase staining. However, we herein report of a 40-year-old woman with the microgranular variant of acute promyelocytic leukemia presenting with weak myeloperoxidase (MPO) staining. The leukemic cells were morphologically similar to monocytic cells, showing distorted-shaped nuclei and weak MPO staining. However, flow cytometry revealed positivity of CD2, CD34, and human leucocyte antigen-DR (HLA-DR) and pointed toward a diagnosis of APL. PML-RARA mRNA detection finally led the patient to a definitive diagnosis. The patient achieved complete remission by induction chemotherapy including tretinoin, cytarabine and idarubicin, and no differentiation syndrome was observed.

[Open Heart Surgery to Remove an Ablation Catheter Entrapped in the Left Ventricle;Report of a Case].

A 66-year-old man underwent catheter ablation for Wolff-Parkinson-White syndrome. When we advanced the ablation catheter clockwise in the left ventricle, it was entrapped and became unable to control. Thus, the patient underwent open heart surgery for catheter removal. During the surgery, the last few millimeters of the catheter were observed entrapped by multiple basal chordae of the posterior mitral valve. We released the catheter safely, and visual inspection of the left ventricle showed no abnormalities. His postoperative course was uneventful. Ablation catheter entrapment in the heart is a rare but severe complication that requires open heart surgery.

[Valve Re-replacement Combined with Patch Enlargement of the Aortic Annulus for Bioprosthetic Valve Deterioration;Report of a Case].

A 42-year-old woman had undergone aortic valve replacement with a 19 mm bioprosthetic valve for aortic stenosis due to a bicuspid valve 8 years before. She was admitted to our hospital for valve re-replacement owing to the prosthetic valve dysfunction. As the patient's valve annulus was markedly thickened owing to pannus formation, we were unable to pass a 19 mm valve sizer through the annulus even after removal of the prosthetic valve and the tissue surrounding the annulus. Valve re-replacement combined with patch enlargement of the aortic annulus was performed to obtain maximally effective orifice area. Her postoperative course was uneventful, and echocardiography revealed no perivalvular leak. In valve re-replacement, it is important to remove the prosthetic valve and the tissue surrounding the annulus to the greatest extent possible and consider patch enlargement of the aortic annulus to avoid patient-prosthesis mismatch in a patient with a small aortic annulus.

Skewed megakaryopoiesis in human induced pluripotent stem cell-derived haematopoietic progenitor cells harbouring calreticulin mutations.

Somatic mutations in the calreticulin (CALR) gene have been found in most patients with JAK2- and MPL-unmutated Philadelphia chromosome-negative myeloproliferative neoplasms (MPNs). It has recently been shown that mutant CALR constitutively activates the thrombopoietin receptor MPL and, thus, plays a causal role in the development of MPNs. However, the roles of mutant CALR in human haematopoietic cell differentiation remain predominantly elusive. To examine the impact of the 5-base insertion mutant CALR gene (Ins5) on haematopoietic cell differentiation, we generated induced pluripotent stem cells from an essential thrombocythaemia (ET) patient harbouring a CALR-Ins5 mutation and from a healthy individual (WT). Megakaryopoiesis was more prominent in Ins5-haematopoietic progenitor cells (Ins5-HPCs) than in WT-HPCs, implying that the system recapitulates megakaryocytosis observed in the bone marrow of CALR-mutant ET patients. Ins5-HPCs exhibited elevated expression levels of GATA1 and GATA2, suggesting a premature commitment to megakaryocytic differentiation in progenitor cells. We also demonstrated that 3-hydroxy anagrelide markedly perturbed megakaryopoiesis, but not erythropoiesis. Collectively, we established an in vitro model system that recapitulates megakaryopoiesis caused by mutant CALR. This system can be used to validate therapeutic compounds for MPN patients harbouring CALR mutations and in detailed studies on mutant CALR in human haematological cell differentiation.