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In haematological malignancies, such as malignant lymphoma, reprogramming of fatty acid metabolism favours tumour cell survival and drug resistance. Hydroxyacyl-CoA dehydrogenase trifunctional multienzyme complex subunit alpha (HADHA), an enzyme involved in fatty acid beta-oxidation (FAO), is overexpressed in high-grade lymphoma and is a predictor of poor prognosis in diffuse large B-cell lymphoma (DLBCL). HADHB forms a heterodimer with HADHA and functions as an FAO enzyme together with HADHA; however, the relevance of its expression in malignant lymphoma is unknown. In this study, we investigated the roles and antitumour effects of HADHB expression in malignant lymphoma. Immunohistochemical analysis showed that HADHB was frequently overexpressed in the high-grade lymphoma subtype. HADHB overexpression was observed in 68% (87/128) of DLBCL cases and was an independent predictor of poor prognosis (p=0.001). In vitro analysis demonstrated that HADHB knockdown suppressed cell proliferation in LCL-K and MD901 cells (p

Succinyl-CoA:3-oxoacid CoA transferase (SCOT, gene symbol OXCT1) deficiency is an autosomal recessive disorder in ketone body utilization that results in severe recurrent ketoacidotic episodes in infancy, including neonatal periods. More than 30 patients with this disorder have been reported and to our knowledge, their heterozygous parents and siblings have had no apparent ketoacidotic episodes. Over 5 years (2008-2012), we investigated several patients that presented with severe ketoacidosis and identified a heterozygous OXCT1 mutation in four of these cases (Case1 p.R281C, Case2 p.T435N, Case3 p.W213*, Case4 c.493delG). To confirm their heterozygous state, we performed a multiplex ligation-dependent probe amplification analysis on the OXCT1 gene which excluded the presence of large deletions or insertions in another allele. A sequencing analysis of subcloned full-length SCOT cDNA showed that wild-type cDNA clones were present at reasonable rates to mutant cDNA clones. Over the following 2 years (2013-2014), we analyzed OXCT1 mutations in six more patients presenting with severe ketoacidosis (blood pH ≦7.25 and total ketone body ≧10 mmol/L) with non-specific urinary organic acid profiles. Of these, a heterozygous OXCT1 mutation was found in two cases (Case5 p.G391D, Case6 p.R281C). Moreover, transient expression analysis revealed R281C and T435N mutants to be temperature-sensitive. This characteristic may be important because most patients developed ketoacidosis during infections. Our data indicate that heterozygous carriers of OXCT1 mutations can develop severe ketoacidotic episodes in conjunction with ketogenic stresses.

We report a case of immunoglobulin G4-related large thoraco-abdominal aortic aneurysm in a 38-year old man. Preoperative contrast-enhanced computed tomography revealed that the mid-descending thoracic aorta was extremely enlarged and the maximum diameter of the aneurysm was 92 mm. The patient underwent thoraco-abdominal aortic replacement through a thoraco-abdominal incision under left heart bypass. The postoperative pathological examination diagnosed immunoglobulin G4-related aortic aneurysm.

The reversed elephant trunk procedure uses an inverted graft for distal aortic replacement before aortic arch replacement in patients with mega aorta, to reduce the risk in the second stage. However, the conventional technique restricts the maximum diameter of the inverted graft to the aortic graft diameter. We employed a beveled reversed elephant trunk procedure to overcome the discrepancy between graft diameters in a 54-year-old woman with a severely twisted ascending aortic graft and enlarging chronic dissection of the aortic arch and descending thoracic aorta. The patient was discharged with a satisfactory repair and no neurologic deficit.

Background Kommerell’s diverticulum is an extremely rare congenital aortic anomaly. Because of its rarity, the optimal surgical strategy for Kommerell’s diverticulum has not been established. In this study, we reviewed our experience of surgical correction of this anomaly. Methods Between 2007 and 2013, we managed 9 surgical cases of Kommerell’s diverticulum; 7 had a right aortic arch with an aberrant left subclavian artery, and 2 had a left aortic arch with an aberrant right subclavian artery. None of these patients had any symptom resulting from structural compression between the aneurysm and the aberrant subclavian artery. All patients underwent surgical treatment to prevent aneurysmal rupture. Six patients had replacement of the thoracic descending aorta and in-situ reconstruction of the aberrant subclavian artery through a right thoracotomy, and 3 underwent the same procedures through a left thoracotomy. Three different methods of extracorporeal circulation were applied, according to the anatomical features of each case. Results There was one hospital death. This patient developed severe cerebral infarction and died of multiple organ failure on the 65th postoperative day. There were no other major complications nor any need for rehospitalization. Conclusion Kommerell’s diverticulum should be treated using an optimal strategy based on each patient’s anatomical features and other characteristics.

To clarify clinical and genetic features of Japanese children with congenital chloride diarrhea (CCD).This was a multi-institutional, retrospective survey of 616 pediatric centers in Japan with identified patients with CCD between 2014 and 2018. Mutations involving SLC26A3 were detected by Sanger sequencing.Thirteen patients met all entry criteria including mutations in SLC26A3, and 14 patients satisfied clinical diagnostic criteria. Homozygous or compound heterozygous mutations in SLC26A3, including 6 novel mutations, were identified in 13 of these 14 patients (93%). The most common (detected in 7 of 13) was c.2063-1gt. Median age at diagnosis was 1 day. Nine of the patients meeting all criteria were diagnosed as neonates (69%). Median follow-up duration was 10 years. When studied, 8 patients had5 stools daily (62%), and all had fewer than in infancy. Only 1 patient had nephrocalcinosis, and 3 (23%) had mild chronic kidney disease. Neurodevelopment was generally good; only 1 patient required special education. Five patients (38%) received long-term sodium, potassium, and chloride supplementation.Early fetal ultrasound diagnosis and prompt long-term sodium, potassium, and chloride supplementation were common management features. Genetic analysis of SLC26A3 provided definitive diagnosis of CCD. In contrast with previously reported localities, c.2063-1gt might be a founder mutation in East Asia.

PURPOSE Endovascular aneurysm repair (EVAR) is a minimally invasive treatment that is becoming standard in abdominal aortic aneurysm treatment. We examine the risk factors of death by comparing the short-term results of abdominal aortic aneurysm by open surgical repair with EVAR. METHODS We performed elective abdominal aortic aneurysm treatment on 122 cases during the period from January 2008 to December 2009. Seventy one cases were treated with open surgical repair while 51 cases were treated with EVAR. RESULTS Compared to the open surgical repair group, the EVAR group was significantly older and had a higher complication rate and past laparotomy rates. No significant difference in hospital deaths was observed between the two groups. Two deaths with thromboembolism due to shaggy aorta were observed in the EVAR group. Two cases in the open surgical repair group developed postoperative myocardial infarction and one death was observed. Both patients underwent coronary artery treatment using drug eluting stents (DES) prior to surgery. CONCLUSION Shaggy aorta has a high possibility of causing thromboembolism and EVAR should not be performed unless there is a considerable reason. In cases in which coronary artery treatment is performed with DES in recent days, EVAR is more preferable.

Purpose To report the early results of use of the Endurant stent graft in the treatment of ruptured abdominal aortic aneurysms (AAAs). Materials and Methods Nine consecutive patients (seven men and two women; mean age, 76 y; range, 65–87 y) underwent endovascular aneurysm repair (EVAR) for a ruptured AAA with the Endurant stent graft between April and December 2012. EVAR was emergent in all cases. Early technical success, clinical success, major complication, and mortality rates were analyzed. Results Intraoperative immediate technical success was achieved in all nine patients. The 30-day clinical success rate was 67% (six of nine patients). The 30-day mortality rate was 33% (three of nine patients). During a mean follow-up of 6 months (range, 3–10 mo), none of the cases required reintervention; there was one late death attributed to probable endograft infection. Conclusions The short-term results of EVAR with the Endurant stent graft in patients with ruptured AAAs are encouraging.

A 65-year-old man with an isolated aneurysm of the proximal right subclavian artery (SCA) (diameter, 50 mm) was successfully treated with a deliberate surgical strategy described here. Because of the occluded left vertebral artery (VA) and poor development of the circle of Willis, the distal portion of the right SCA was bypassed from the ascending aorta before resecting the aneurysm in order to maintain blood flow to the brain through the right VA. Consequently, the patient recovered without neurological complications. We conclude that conventional surgery remains effective for complex vascular diseases even in the era of advanced endovascular surgeries.

A 69-year-old man was admitted to our hospital with acute epigastric discomfort and subsequent paraplegia. Computed tomography revealed acute type B aortic dissection with a thrombosed false lumen. Magnetic resonance imaging did not reveal spinal cord infarction. Paraplegia resolved completely within 1 h. However, on the following day, the patient developed motor impairment in the left leg, sensory disorder of the bilateral legs and urinary retention. The symptoms gradually improved with conservative medical therapy. Magnetic resonance imaging on hospitalization Day 20 revealed spinal cord infarction limited to the right posterior area at level T7/T8 and the conus medullaris. The patient was discharged 44 days after admission. The presented case is notable for its atypical presentation of spinal cord infarction resulting from acute aortic dissection. The aetiology of neurological symptoms, especially that of lower extremity monoplegia, remained undiagnosed.

We previously performed genetic analysis in six unrelated families with infantile limb pain episodes, characterized by cold-induced deterioration and mitigation in adolescence, and reported two new mutations p.R222H/S in SCN11A responsible for these episodes. As no term described this syndrome (familial episodic pain: FEP) in Japanese, we named it as”小児四肢疼痛発作症”. In the current study, we recruited an additional 42 new unrelated Japanese FEP families, between March 2016 and March 2018, and identified a total of 11 mutations in SCN11A: p.R222H in seven families, and p.R225C, p.F814C, p.F1146S, or p.V1184A, in independent families. A founder mutation, SCN11A p.R222H was confirmed to be frequently observed in patients with FEP in the Tohoku region of Japan. We also identified two novel missense variants of SCN11A, p.F814C and p.F1146S. To evaluate the effects of these latter two mutations, we generated knock-in mouse models harboring p.F802C (F802C) and p.F1125S (F1125S), orthologues of the human p.F814C and p.F1146S, respectively. We then performed electrophysiological investigations using dorsal root ganglion neurons dissected from the 6–8 week-old mice. Dissected neurons of F802C and F1125S mice showed increased resting membrane potentials and firing frequency of the action potentials (APs) by high input–current stimulus compared with WT mice. Furthermore, the firing probability of evoked APs increased in low stimulus input in F1125S mice, whereas several AP parameters and current threshold did not differ significantly between either of the mutations and WT mice. These results suggest a higher level of excitability in the F802C or F1125S mice than in WT, and indicate that these novel mutations are gain of function mutations. It can be expected that a considerable number of potential patients with FEP may be the result of gain of function SCN11A mutations.

Nephrin is an essential structural component of the glomerular slit diaphragm (SD), a highly organized intercellular junction that constitutes the ultrafiltration barrier of the kidney. Recent studies have identified two additional nephrin-interacting SD proteins (NEPH1 and NEPH2), suggesting that the zipper-like pattern of the SD is formed through complex intra- and intermolecular interactions of these proteins. However, the complexity of the SD structure suggests that additional SD components remain to be discovered. In this study, we identified galectin-1 (Gal-1) as a new component of the SD, binding to the ectodomain of nephrin. Using dual-immunofluorescence and confocal microscopy and dual-immunoelectron microscopy, we found Gal-1 co-localizing with the ectodomain of nephrin at the SD in normal human kidney. By immunoprecipitation and surface plasmon resonance, we confirmed a direct molecular interaction between Gal-1 and nephrin. Moreover, recombinant Gal-1 induced tyrosine phosphorylation of the cytoplasmic domain of nephrin and activation of the extracellular signal-regulated kinase 1/2 in podocytes. We also showed that podocytes are a major site of biosynthesis of Gal-1 in the glomerulus and that the normal expression patterns and levels of Gal-1 are altered in patients with minimal change nephrotic syndrome. Finally, in puromycin aminonucleoside-induced rat nephrosis, an apparent reduction in the levels of Gal-1 and nephrin around the onset of heavy proteinuria was also revealed. Our data present Gal-1 as a new extracellular ligand of nephrin localized at the glomerular SD, and provide further insight into the complex molecular organization, interaction, and structure of the SD, which is an active site of intracellular signaling necessary for podocyte function.

Syphilitic aortitis is usually associated with thoracic aortic saccular aneurysm, aortic regurgitation and coronary ostial stenosis. However, syphilitic aneurysms have rarely been reported today. Here, we report a patient with ascending aortic aneurysm with aorta-superior vena cava (SVC) fistula with positive syphilitic test. A 52-year-old man was admitted to our institution with a giant ascending aortic aneurysm complicated with SVC syndrome. Computed tomography revealed a giant ascending aneurysm 79 mm in diameter. The result of serodiagnostic tests for syphilis had not been judged yet preoperatively. Total arch replacement concomitant with elephant trunk was performed. Intraoperatively, we detected the ascending aorta to SVC fistula. Postoperatively, we suspected the syphilitic aneurysm strongly, because preoperative serodiagnostic test was concluded to be positive. However, histological examination did not show typical syphilitic features. The patient remains asymptomatic 1 year later. Although extremely rarely today, syphilitic aneurysm should be still considered in the differential diagnosis of ascending aortic aneurysm.

Background Although the results of surgical repair of thoracoabdominal aortic aneurysm continue to improve, the incidence of paraplegia remains within a wide range depending on each institution. The purpose of this study was to find predictors of paraplegia following thoracoabdominal aortic aneurysm repair in our institute, using the current spinal cord protection strategies. Methods From January 2007 to December 2011, 200 consecutive patients underwent thoracoabdominal aortic aneurysm repair. Of these, 24 (12%) had Crawford extent I repair, 82 (41%) had extent II, 51 (25.5%) had extent III, 10 (5%) had extent IV, and 33 (16.5%) had extent V (modified by Safi). Aortic dissection was present in 101 (50.5%) patients. Adjuncts used during the procedures included left heart bypass in all patients, cerebrospinal fluid drainage in 164 (82%), and intercostal artery reimplantation in 76 (38%). Results There were 20 (10%) hospital deaths including 6 (3%) within 30 days; hospital mortality was 8.8% in elective operations. Postoperative complications included paraplegia in 17 (8.5%) patients, stroke in 5 (2.5%), and acute renal failure requiring dialysis in 5 (2.5%). Logistic regression analysis revealed that significant factors for the development of paraplegia were preoperative hypotension ( p = 0.005, odds ratio 18.5), intraoperative hypotension ( p = 0.001, odds ratio 77.6), and an open distal anastomosis technique ( p = 0.012, odds ratio 4.6). Conclusions The predictors of postoperative paraplegia in our institution were perioperative hypotension and an open distal anastomosis technique. Avoidance of these risk factors might diminish the incidence of postoperative paraplegia.

The study aim was to comprehend the outcomes of surgery for prosthetic valve endocarditis (PVE) over 25 years and to identify predictors for patient survival.A total of 47 consecutive patients (19 males, 28 females; mean age 67.0 +/- 11.5 years) whounderwent surgery for PVE between 1986 and 2011 was analyzed. Typically, PVE appeared at 4.2 +/- 6.2 years after valve replacement. Preoperative and postoperative clinical variables were evaluated; the mean follow up was 6.4 +/- 5.3 years.The incidence of PVE was 3.9% for 1,185 cases of valve replacement through the study period. Operative mortality was 17.0%. NYHA functional class IV (p = 0.01), preoperative shock (p = 0.03) and renal failure (p = 0.02) were each independent predictors of operative mortality. Survival was 69.1 +/- 9.3% at 10 years and 59.2 +/- 12.1% at both 15 and 20 years. Preoperative impaired left ventricular function (p = 0.02) and preoperative renal failure (p = 0.04) were independent predictors of late mortality. Freedom from recurrent PVE remained at 82.5 +/- 6.0% from two years up to 20 years after surgery. Initial infective endocarditis (p = 0.03) and postoperative heart failure (p = 0.04) were predictors of recurrent PVE. Freedom from reoperation was 84.8 +/- 5.7% at 10 years, and 72.6 +/- 12.2% at both 15 and 20 years.This extensive examination revealed that critical preoperative conditions determine not only short-term but also long-term mortality after surgery to treat PVE. Hence, a timely surgical intervention and close follow up are crucial for patient survival.

Prosthetic valve endocarditis (PVE) is considered a time-related event. The study aim was to compare the clinical characteristics and outcomes of early- and late-onset PVE, and to investigate potential preventive measures for each condition.A total of 47 consecutive patients undergoing surgery for PVE between January 1986 and December 2011 were analyzed retrospectively, and classified as an early-onset group (n = 26; PVE occurring within 12 months after previous surgery) and late-onset group (n = 21; PVE occurring after 12 months).The prosthetic valve position significantly affected the incidence of endocarditis: 21 cases (80.7%) in the early-onset group had infected aortic prostheses, while 18 (85.7%) in the late-onset group had infected mitral prostheses (p = 0.028). PVE significantly affected bioprosthetic valves in the early-onset group (18 cases, 69.2%) and mechanical valves in the late-onset group (17 cases, 80.9%) (p0.01). Staphylococcus spp. infections were predominant in the early-onset group (21 cases, 80.7%), and Streptococcus spp. in the late-onset group (five cases, 23.8%) (p = 0.03). Operative deaths occurred in both the early-onset (n = 6; 23.0%) and late-onset (n = 2; 9.5%) groups (p = 0.11). The long-term mortality in the early-onset and late-onset groups, respectively, was 40.3 +/- 17.7% and 85.1 +/- 7.9% at 10 years, and 40.3 +/- 17.7% and 72.9 +/- 13.1% at 15 years (p 0.047). Freedom from recurrent endocarditis after two years in the early- and late-onset groups, respectively, was 67.8 +/- 10.1% and 88.8 +/- 7.4% (p = 0.048).Clinical characteristics and outcomes differed significantly between early- and late-onset PVE. The clinical outcomes of patients with early PVE tend to be serious, and therefore stringent care should be taken to avoid contamination during the initial surgery and hence to reduce the incidence of the condition.

Haemolytic anaemia after acute aortic dissection surgery is extremely rare. We report 4 cases of haemolytic anaemia with different aetiologies.Four patients underwent emergency operation for acute type A aortic dissection and subsequently developed haemolytic anaemia.Case 1: a 41-year old man underwent hemiarch replacement. We performed total arch replacement 3 years postoperatively, which revealed that haemolytic anaemia was induced by proximal anastomotic stenosis caused by inverted internal felt strip. Case 2: a 28-year old man diagnosed with Marfan syndrome underwent total arch replacement. Five months postoperatively, we noted severe stenosis at the previous distal anastomotic site, which caused the haemolytic anaemia, and performed descending thoracic aortic replacement for a residual dissecting aneurysm. Case 3: a 49-year old man underwent hemiarch replacement. Three years postoperatively, we performed total arch replacement for a residual dissecting aortic arch aneurysm and repaired a kinked graft responsible for haemolytic anaemia. Case 4: a 42-year old man underwent total arch replacement. Eighteen months later, we performed descending thoracic aortic replacement. We repaired a portion of the ascending aorta as haemolityc anaemia was induced by kinking of a total arch replacement redundant graft.All the haemolityc anaemia patients were successfully released after surgical reintervention.

A rare case of an aneurysmal Kommerell's diverticulum in a right-sided aortic arch was successfully treated using a hybrid procedure comprising total arch replacement and percutaneous stent grafting. A 65-year-old man with dysphagia was diagnosed with an ectatic right-sided aortic arch and a saccular aneurysm of the Kommerell's diverticulum. Since its radical resection during a single surgery was unfeasible because of its complex configuration, a 2-stage procedure was adopted.

A 70-year-old man underwent graft replacement for infrarenal abdominal aortic aneurysm, 50 mm in diameter. Postoperatively, he suffered from bilateral lower extremital ischemia. Although he underwent emergency embolectomy of both legs under general anesthesia, severe purplish discoloration of the distal lower extremities developed, and acute renal dysfunction occurred. He was diagnosed with cholesterol crystal embolization syndrome (CCE). We initiated intravenous steroid therapy and infused prostagrandin intraarterially and conducted low density lipoprotein (LDL) apheresis. However, his renal function did not improve and his bilateral toes became necrotic completely. Multiple organ failure rapidly worsened and he died at 38 days after surgery. CCE complicated with severe renal dysfunction is a lethal iatrogenic complication after surgery for abdominal aortic aneurysm. Because the number of CCE is likely to increase in the near future, we should study about CCE more seriously.

An 83-year-old woman, who had suffered from idiopathic thrombocytopenic purpura (ITP), was admitted to our hospital because of cardiac heart failure and chest pain. The platelet was 42 x 10(4) in microl. Echocardiography revealed moderate aortic stenosis and regurgitation and left ventricular dysfunction. Preoperatively, we tapered oral steroid and administered high-dose immunoglobulin intravenously. Intraoperatively, we found quadricuspid aortic valve and the rudimentary accessory cusp was located between the right coronary cusp and noncoronary cusp. Aortic valve replacement was performed with bioprosthetic valve. The postoperative course was uneventful. Postoperative echocardiography revealed no perivalvular leakage. Preoperative administration of high-dose immunoglobulin and intraoperative platelet transfusion is very effective to minimize hemorrhagic complication in patients with ITP. We herein report an extremely rare quadricuspid aortic valve complicated with ITP.

Objective: Although the left atrial appendage (LAA) is excised to prevent thrombosis in the maze procedure, it remains unclear whether LAA is retained in expectation of LAA booster function. Therefore, we quantitatively assessed LAA size and function after the maze procedure in patients with chronic atrial fibrillation (AF) and mitral valve disease (MVD), and compared with those in patients with sinus rhythm after coronary artery bypass grafting (CABG). Methods: We studied 23 patients (maze group: 65.0 9.2 (SD) years) undergoing the maze procedure for chronic AF and mitral valve surgery and 16 patients having sinus rhythm after CABG (CABG group: 66.5 9.3 years). The maze procedure was conducted by radiofrequency (RF) ablation and LAA was preserved in all cases. Left atrium (LA) and LAA volume and booster function were quantitatively evaluated by multidetector computed tomography (MDCT) at 11.7 10.4 months (maze group) and 16.8 19.9 months (CABG group) after the surgery. Results: In all 23 patients of the maze group, sinus rhythm was well restored. LAA was clearly visualised without thrombi in all 39 patients. The maximal LA volume in the maze group was 128.8 54.6 ml, being larger than 105.3 36.1 ml in the CABG group. LA ejection fraction (EF) in the maze group was 16.1 7.0%, being significantly lower than 26.8 8.7% in the CABG group. Meanwhile, the maximal LAA volume inthe mazegroup wassignificantlylarger(16.9 7.3 ml vs 8.4 4.7 ml), but LAA EF (34.1 12.8% vs 36.1 7.4%) wascomparable inthe two groups. Conclusion: LAA largely contributes to LA booster function, particularly in the maze group, because LA booster function is deteriorated in this group of patients. # 2010 European Association for Cardio-Thoracic Surgery. Published by Elsevier B.V. All rights reserved.

Proteins are modified and folded within the endoplasmic reticulum (ER). When the influx of proteins exceeds the capacity of the ER to handle the load, the ER is "stressed" and protein biogenesis is affected. We have previously shown that the induction of ER stress by ATP depletion in podocytes leads to mislocalization of nephrin and subsequent injury of podocytes. The aim of the present study was to determine whether ER stress is associated with proteinuria in vivo and whether the immunosuppressant mizoribine may exert its antiproteinuric effect by restoring normal nephrin biogenesis. Induction of nephrotic-range proteinuria with puromycin aminonucleoside in mice increased expression of the ER stress marker GRP78 in podocytes, and led to the mislocalization of nephrin to the cytoplasm. In vitro, mizoribine, through a mechanism likely dependent on the inhibition of inosine 5'-monophosphate dehydrogenase (IMPDH) activity in podocytes, restored the intracellular energy balance by increasing levels of ATP and corrected the posttranslational processing of nephrin. Therefore, we speculate that mizoribine may induce remission of proteinuria, at least in part, by restoring the biogenesis of slit diaphragm proteins in injured podocytes. Further understanding of the ER microenvironment may lead to novel approaches to treat diseases in which abnormal handling of proteins plays a role in pathogenesis.

A 63-year-old female had been treated for liver cirrhosis and hepatocellular carcinoma (HCC) since 3 years before. She developed symptoms of dyspnea and echocardiography revealed a large tumor in the right atrium. The stalk of tumor was attached to the intraatrial septum just above the tricuspid valve and the tumor was floating between the right atrium and the right ventricle according to cardiac rhythm. The size of tumor was 30 x 15 mm in diameter. She was admitted to our hospital for emergency operation. She was operated for cardiac tumor under cardiopulmonary bypass successfully and the postoperative course was uneventful. But the pathology reported direct intracavitary metastasis of HCC without intravascular involvement. She was discharged on the 7th postoperative day for the treatment of HCC.