Wnt target gene activation requires ß-catenin separation into biomolecular condensates.

The Wnt/ß-catenin signaling pathway plays numerous essential roles in animal development and tissue/stem cell maintenance. The activation of genes regulated by Wnt/ß-catenin signaling requires the nuclear accumulation of ß-catenin, a transcriptional co-activator. ß-catenin is recruited to many Wnt-regulated enhancers through direct binding to T-cell factor/lymphoid enhancer factor (TCF/LEF) family transcription factors. ß-catenin has previously been reported to form phase-separated biomolecular condensates (BMCs), which was implicated as a component of ß-catenin's mechanism of action. This function required aromatic amino acid residues in the intrinsically disordered regions (IDRs) at the N- and C-termini of the protein. In this report, we further explore a role for ß-catenin BMCs in Wnt target gene regulation. We find that ß-catenin BMCs are miscible with LEF1 BMCs in vitro and in cultured cells. We characterized a panel of ß-catenin mutants with different combinations of aromatic residue mutations in human cell culture and Drosophila melanogaster. Our data support a model in which aromatic residues across both IDRs contribute to BMC formation and signaling activity. Although different Wnt targets have different sensitivities to loss of ß-catenin's aromatic residues, the activation of every target examined was compromised by aromatic substitution. These mutants are not defective in nuclear import or co-immunoprecipitation with several ß-catenin binding partners. In addition, residues in the N-terminal IDR with no previously known role in signaling are clearly required for the activation of various Wnt readouts. Consistent with this, deletion of the N-terminal IDR results in a loss of signaling activity, which can be rescued by the addition of heterologous IDRs enriched in aromatic residues. Overall, our work supports a model in which the ability of ß-catenin to form biomolecular condensates in the nucleus is tightly linked to its function as a transcriptional co-regulator.

Successful Endovascular Management of Pseudoaneurysm following Transarterial Chemoembolization: A Case Report.

Background and Objectives: Transarterial chemoembolization (TACE) is a widely accepted treatment for hepatocellular carcinoma (HCC). Regarding TACE, arterial injuries, such as hepatic artery spasm or dissection, can also occur, although pseudoaneurysms are rare. We report a case of pseudoaneurysm following TACE. Materials and Methods: A 78-year-old man had been undergoing TACE for HCC in segment 8 of the liver for the past 5 years, with the most recent TACE procedure performed approximately 1 month prior. He presented to the emergency department with melena that persisted for 5 days. Computed tomography revealed a pseudoaneurysm in the S8 hepatic artery with hemobilia. Results: the pseudoaneurysm was successfully treated by N-Butyl-cyanoacrylate glue embolization. Conclusions: In patients that have undergone TACE presenting with melena and hemobilia identified on CT, consideration of hepatic artery pseudoaneurysm is crucial. Such cases can be safely and effectively treated with endovascular managements.

Inferior Vena Cava Stenosis Following Orthotopic Liver Transplantation: Differentiating Points from False Positives.

Orthotopic liver transplantation has become the treatment of choice for patients with end-stage liver disease. Various early or delayed vascular complications, including arterial pseudoaneurysm, thrombosis, or stenosis, and venous stenosis or occlusion, may lead to graft failure. Early detection and prompt management of such complications are essential to achieve successful transplantation and prevent the need for retransplantation. This report presents differentiating points, using computed tomography and digital subtraction angiography findings and measurement of pressure gradient across the stenotic lesion, that require immediate intervention in patients with inferior vena cava stenosis after orthotopic liver transplantation.

Factors associated with increased risk of peritoneal seeding after radiofrequency ablation for hepatocellular carcinoma.

PURPOSE: To evaluate the incidence, risk factors, and prognosis associated with peritoneal seeding after percutaneous radiofrequency ablation (RFA) for HCC, focusing on viable tumors after previous locoregional treatment, including TACE and RFA. METHODS: Exactly 290 patients (mean age, 67.9 years ± 9.74; 223 men) with 383 HCCs (mean size, 15.9 mm ± 5.49) who underwent RFA between June 2012 and December 2019 were included in this retrospective study. Among them, 158 had history of previous treatment (mean number, 1.3 ± 1.8) with 109 viable HCCs. Cumulative seeding after RFA was estimated using the Kaplan-Meier method. Independent factors affecting seeding were investigated using multivariable Cox proportional hazards regression analysis. RESULTS: Median follow-up was 1175 days (range: 28-4116). Seeding incidence was 4.1 (12/290) and 4.7% (17/383) per patient and tumor, respectively. The median time interval between RFA and detection of seeding was 785 days (range: 81-1961). Independent risk factors for seeding included subcapsular tumor location (hazard ratio [HR] 4.2; 95% confidence interval [CI] 1.4, 13.0; p = 0.012) and RFA for viable HCC after previous locoregional treatment (HR 4.5; 95% CI 1.7, 12.3; p = 0.003). Subgroup analysis for viable tumors, revealed no significant difference in cumulative seeding rates between the TACE and RFA groups (p = 0.078). Cumulative overall survival rates differed significantly between patients with and without seeding metastases (p < 0.001). CONCLUSION: Peritoneal seeding after RFA is a rare, delayed complication. Subcapsular-located and viable HCC after previous locoregional treatment are potential risk factors for seeding. Seeding metastases could affect the prognosis of patients who cannot receive local therapy.

Treating Sudden Onset Hepatic Encephalopathy with Coil Embolization in a Patient with a Congenital Intrahepatic Portosystemic Venous Shunt: A Case Report.

Intrahepatic portosystemic venous shunt (IPSVS) is a rare vascular abnormality that involves abnormal communication between the intrahepatic portal vein and systemic veins, such as the hepatic vein or inferior vena cava. Patients with IPSVS are typically asymptomatic, and IPSVS is incidentally discovered via imaging while evaluating other diseases. However, endovascular closure of the shunt should be considered in symptomatic patients with a high-flow shunt. This report presents a patient with congenital IPSVS with sudden onset hepatic encephalopathy treated using percutaneous transhepatic embolization.

Efficacy of single-session 99.5% ethanol sclerotherapy for incidentally found simple renal cysts.

Simple renal cysts are the most common masses in the kidney. Most are asymptomatic and are incidentally detected on imaging examinations performed for other reasons. This study aimed to compare the results of 40 and 120 minutes ethanol sclerotherapies that were performed in a single session to treat incidentally found simple renal cysts. We retrospectively reviewed 63 renal cysts in 62 patients treated by single session percutaneous ethanol sclerotherapy. Thirty-one patients with 32 cysts underwent a 40 minutes sclerotherapy (group A), and 31 patients with 31 cysts underwent a 120 minutes retention technique (group B). Under ultrasonographic and fluoroscopic guidance, cystic fluid was completely aspirated, and 50% of the aspirated volume was replaced with 99.5% ethanol (a maximum of 100 mL). Imaging follow-up of the patients was performed 3 months after sclerotherapy. The technical success rates were 100% in both groups. Eighteen patients (29.0%) were symptomatic (flank pain or discomfort). Indications of the other patients were large cysts (>5 cm; 46%) and an increment in the diameter on serial studies (25.4%). A significant difference between the 2 groups in terms of age, cyst diameter, volume of aspirated fluid, volume of injected ethanol, and percentage of reduction in cyst diameter (P > .05) was not found. After treatment, flank pain or discomfort resolved in 17 of 18 (94.4%) symptomatic patients. One patient complained of persistent flank pain; however, no significant abnormality was detected on post-procedural computed tomography images. There were no other complications after therapy in the 2 groups. Single session ethanol sclerotherapy with a 40 minutes retention technique is an effective, safe, and cost-effective method for the treatment of incidentally found simple renal cysts. Although the procedural time was reduced, there was no significant difference in therapeutic efficacy between the 40 and 120 minutes therapies.

Percutaneous N-Butyl-Cyanoacrylate Embolization for Treating Ruptured Pancreaticoduodenal Aneurysm: A Case Report.

Background and Objectives: Pancreaticoduodenal artery aneurysms are rare visceral artery aneurysms. Interventional treatments, including transcatheter embolization, have an acceptable success rate. We report a case of ruptured pancreaticoduodenal aneurysm that was successfully treated with percutaneous N-Butyl-cyanoacrylate (NBCA) embolization after failed transcatheter embolization. Materials and Methods: A 53-year-old man presented to the emergency department with abdominal pain. Computed tomography (CT) revealed a ruptured aneurysm in the inferior pancreaticoduodenal artery (IPDA) with retrohemoperitoneum. The patient underwent percutaneous NBCA embolization after transcatheter embolization failure. Results: On CT, the pancreaticoduodenal aneurysm was completely embolized. No additional bleeding events occurred. Conclusions: Percutaneous NBCA embolization is safe and effective for treating patients with ruptured pancreaticoduodenal aneurysms after failed transcatheter embolization.

Radiologic placement of Hickman catheters using intravenous sedation in pediatric patients under 20 kg.

ABSTRACT: Surgeons generally perform Hickman catheter insertion in children under general anesthesia. At times, it is difficult to perform procedures with an anesthesiologist for an interventional radiologist. Several diagnostic and therapeutic procedures are efficiently and safely conducted using intravenous (IV) sedation in children with a pediatrician. This study aims to evaluate the efficacy and safety of radiologically placed Hickman catheters using IV sedation in children under 20 kg.Fifty-nine catheters were inserted in 45 children under IV sedation. With continuous monitoring of vital signs, IV midazolam and ketamine were slowly infused by a pediatrician. Mean age and body weights were 3.2 years and 15.2 kg, respectively. Acute leukemia was the most common disease for the procedure (72.9%). The location of the catheter tip was evaluated by measuring the height of the thoracic vertebra.Technical success rate was 100%, and IV sedation-related complications did not occur. The right internal jugular vein was accessed for 51 catheters (86.4%), and the mean procedure time was 21.5 minutes. The 2 vertebral body units below the carina were the cavoatrial junction on a fluoroscopy image. Mean catheter life was 285 days, and catheters were removed post-treatment (35.6%). During follow-up, complications occurred in 29 cases (1.72 per 1000 catheter-days). Catheter-related infections were suspected in 4 patients (6.8%), with 1 positive result.Radiological Hickman catheter placement in children under 20 kg using IV sedation by pediatricians is effective and safe, with minimal complications. The carina is a landmark to estimate the cavoatrial junction in pediatric patients.

A Paradigm Shift in Dyslipidemia Management in Primary Care: A 12-Month Cohort Study.

PURPOSE: LDL-lowering therapy is beneficial to reduce the risk of cardiovascular disease (CVD). Higher statin doses lower LDL-C levels and prevent CVD; however, they increase adverse events, such as muscle-related adverse events and new-onset diabetes mellitus (DM). Ezetimibe combined with statin therapy improves LDL-C-lowering levels and tolerability in patients with established CVD. We aimed to analyze the efficacy and safety of a fixed-dose rosuvastatin and ezetimibe (R+E) combination therapy in intermediate-risk patients with hypercholesterolemia and no DM after 12 months of visiting a primary physician. METHODS: This multicenter, open-label, single-arm, prospective observational study involved 5717 patients from 258 primary health care centers in Korea enrolled between 2016 and 2018. Patients had no DM or previous CVD but had cardiovascular risk factors and were taking a statin or a fixed-dose combination of E (10 mg) + R (5, 10, or 20 mg). We analyzed 700 patients using propensity score matching. FINDINGS: A fixed-dose R+E combination therapy significantly reduced LDL-C in 5/10 mg R+E (29.35%), 10/10 mg R+E (36.19%), and 20/10 mg R+E (41.83%) compared with statin monotherapy (19.09%) at 12-month follow-up (P = 0.017). Compared with statin monotherapy, HDL-C levels increased in 5/10 mg R+E (mean change at 12 months; P = 0.004), and triglyceride levels decreased in 10/10 mg R+E (mean change at 12 months; P = 0.033). The fixed-dose R+E combination therapy was associated with fewer adverse events and a neutral effect on glucose deterioration compared with statin monotherapy at 12 months of follow-up. IMPLICATIONS: In a possible paradigm shift, a fixed-dose R+E combination therapy may be beneficial for primary cardiovascular prevention with potent LDL-lowering efficacy and tolerability; however, further large prospective studies are needed.

Stent graft treatment of an ilioenteric fistula secondary to radiotherapy: a case report.

Fistulas between the arteries and the gastrointestinal tract are rare but can be fatal. We present a case of an ilioenteric fistula between the left external iliac artery and sigmoid colon caused by radiotherapy for cervical cancer, which was treated with endovascular management using a stent graft. A 38-year-old woman underwent concurrent chemoradiotherapy for cervical cancer recurrence. Approximately 9 months later, the patient suddenly developed hematochezia. On her first visit to the emergency room of our hospital, computed tomography (CT) images did not reveal extravasation of contrast media. However, 8 hours later, she revisited the emergency room because of massive hematochezia with a blood pressure of 40/20 mmHg and a heart rate of 150 beats per minute. At that time, CT images showed the presence of contrast media in almost the entire colon. The patient was referred to the angiography room at our hospital for emergency angiography. Inferior mesenteric arteriography did not reveal any source of bleeding. Pelvic arteriography showed contrast media extravasation from the left external iliac artery to the sigmoid colon; this was diagnosed as an ilioenteric fistula and treated with a stent graft. When the bleeding focus is not detected on visceral angiography despite massive arterial bleeding, pelvic arteriography is recommended, especially in patients with a history of pelvic surgery or radiotherapy.

Characteristics and efficacy of fish-derived gelatin microparticles as an embolic agent in a rabbit renal model: regulation of the degradation period by molecular weight.

PURPOSE: To evaluate the embolic effect of fish-derived gelatin microparticles (GMPs) and compare the degradation periods and biocompatibilities of different molecular weight (MW) GMPs in a rabbit model. METHODS: GMPs were designed to degrade within 21 days (high MW GMP, 15-30 kDa) and 2 days (low MW GMP, 5-15 kDa) in vivo. Renal arteries of 24 rabbits were embolized using both high and low MW GMPs (155-350 µm). Rabbits were sacrificed either immediately after embolization, or after follow-up (F/U) angiogram on days 2 and 21 of embolization, respectively (4 rabbits in each of the 6 subgroups). Pathological changes of recanalized vessels were evaluated using the Banff classification. For the in vitro study, each type of GMP was mixed with normal saline and morphological changes were compared for 14 days. RESULTS: Fish-derived GMPs showed effective embolization. On 2-day F/U angiography, occluded vessels were more recanalized to the peripheral branches in low MW group. On day 21, a parenchymal perfusion defect recovered to a greater extent in low MW group than that in high MW group. Mean Banff scores for intimal arteritis on 2-day F/U and interstitial fibrosis on 21-day F/U were higher in high MW group (1.75 ± 0.58 vs. 0.19 ± 0.4 and 2.56 ± 0.63 vs. 0.88 ± 0.89; P < .001). On in vitro assessment, low MW GMP lost the spherical shape and degraded, and was invisible on microscopy on day 6, whereas high MW GMP was only partially degraded after 2 weeks. CONCLUSION: Fish-derived GMPs showed effective embolization in a rabbit model. Low MW GMPs degraded within 2 days with a low inflammatory response.

Plug-assisted retrograde transvenous obliteration via gastrocaval shunt for the gastric variceal bleeding: A case report.

RATIONALE: Most gastric varices at the fundus drain into the left renal vein via the gastrorenal shunt (80-85% of cases) or the inferior vena cava via the gastrocaval shunt (10-15%). Therefore, plug-assisted retrograde transvenous obliteration (PARTO) is usually performed via a gastrorenal shunt. Here, we report a case of gastric varix treated with PARTO via a gastrocaval shunt. PATIENT CONCERNS: A 46-year-old woman with hepatitis B virus and liver cirrhosis visited the emergency room in our hospital with the main symptom of hematemesis and hematochezia. DIAGNOSES: Endoscopy and computed tomography (CT) revealed a gastric varix and thrombotic-occluded transjugular intrahepatic portosystemic shunt (TIPS) stent. INTERVENTIONS: The patient underwent PARTO via a gastrocaval shunt to manage gastric variceal bleeding after failed TIPS revision. OUTCOMES: On CT, the gastric varix completely disappeared. The patient did not experience any additional bleeding events. LESSONS: PARTO via a gastrocaval shunt is safe and effective.

PI3K Promotes Basal Cell Carcinoma Growth Through Kinase-Induced p21 Degradation.

Basal cell carcinoma (BCC) is a locally invasive epithelial cancer that is primarily driven by the Hedgehog (HH) pathway. Advanced BCCs are a critical subset of BCCs that frequently acquire resistance to Smoothened (SMO) inhibitors and identifying pathways that bypass SMO could provide alternative treatments for patients with advanced or metastatic BCC. Here, we use a combination of RNA-sequencing analysis of advanced human BCC tumor-normal pairs and immunostaining of human and mouse BCC samples to identify a PI3K pathway expression signature in BCC. Pharmacological inhibition of PI3K activity in BCC cells significantly reduces cell proliferation and HH signaling. However, treatment of Ptch1fl/fl ; Gli1-CreERT2 mouse BCCs with the PI3K inhibitor BKM120 results in a reduction of tumor cell growth with no significant effect on HH signaling. Downstream PI3K components aPKC and Akt1 showed a reduction in active protein, whereas their substrate, cyclin-dependent kinase inhibitor p21, showed a concomitant increase in protein stability. Our results suggest that PI3K promotes BCC tumor growth by kinase-induced p21 degradation without altering HH signaling.

Long-Term Clinical and Radiologic Outcomes after Stent-Graft Placement for the Treatment of Late-Onset Post-Pancreaticoduodenectomy Arterial Hemorrhage.

Purpose: To evaluate the long-term radiologic and clinical outcomes of stent-graft placement for the treatment of post-pancreaticoduodenectomy arterial hemorrhage (PPAH) based on the imaging findings of stent-graft patency and results of liver function tests. Materials and Methods: We retrospectively reviewed the medical records of nine consecutive patients who underwent stent-graft placement for PPAH between June 2012 and May 2017. We analyzed the immediate technical and clinical outcomes and liver function test results. Stent-graft patency was evaluated using serial CT angiography images. Results: All stent-grafts were deployed in the intended position for the immediate cessation of arterial hemorrhage and preservation of hepatic arterial blood flow. Technical success was achieved in all nine patients. Eight patients survived after discharge, and one patient died on postoperative day 28. The median follow-up duration was 781 days (range: 28-1766 days). Follow-up CT angiography revealed stent-graft occlusion in all patients. However, serum aspartate aminotransferase or alanine aminotransferase levels in all patients were well below those observed in hepatic infarction cases. Conclusion: Stent-graft placement is a safe and effective treatment method for acute life-threatening PPAH. Liver function and distal hepatic arterial blood flow were maintained postoperatively despite the high incidence of stent-graft occlusion observed on follow-up CT.

Retrograde transvenous obliteration for the prevention of variceal rebleeding in patients with portal vein thrombosis: a multicenter study.

OBJECTIVES: To evaluate the effectiveness of retrograde transvenous obliteration (RTO) for the prevention of variceal rebleeding in cirrhotic patients with portal vein thrombosis (PVT). METHODS: Consecutive cirrhotic patients with PVT who underwent RTO for the prevention of variceal rebleeding between January 2002 and June 2019 were included in this multicenter retrospective study. The primary outcome measure was rebleeding. The secondary outcome measures were survival, other complications of portal hypertension, liver function, and PVT. RESULTS: Forty-five patients (mean age, 66.0 ± 10.6 years; mean Model for End-Stage Liver Disease (MELD) score, 13.9 ± 5.5) were included. The 1-year actuarial probability of remaining free of rebleeding was 92.8 ± 4.0%. The 6-week, 1-year, and 3-year actuarial probabilities of survival were 79.8 ± 6.0%, 48.8 ± 7.7%, and 46.1 ± 7.9%, respectively. MELD score (hazard ratio (HR), 1.09 (95% confidence interval (CI), 1.01-1.17); p = .013) and ascites (HR, 2.84 (95% CI, 1.24-6.55); p = .014) were identified as significant predictors of survival. The 1-year actuarial probabilities of remaining free of new or worsening ascites and esophageal varices were 81.2 ± 8.7% and 89.2 ± 6.0%, respectively. No patients had overt hepatic encephalopathy during follow-up. MELD score significantly increased by a mean of 3.8 (95% CI, 1.7-6.0) at 3 months (p = .001). PVT had improved in 32.0%, worsened in 12.0%, and remained unchanged in 56.0% of patients at 3 months. CONCLUSION: RTO may be effective for the prevention of variceal rebleeding in cirrhotic patients with PVT. KEY POINTS: • Retrograde transvenous obliteration may prevent variceal rebleeding in cirrhotic patients with portal vein thrombosis. • The risks of other complications of portal hypertension may not be high after retrograde transvenous obliteration in cirrhotic patients with portal vein thrombosis. • Portal vein thrombosis may improve in approximately one-third of cirrhotic patients within 3 months after retrograde transvenous obliteration.

Safety, Efficacy, and Patient Satisfaction with Initial Peripherally Inserted Central Catheters Compared with Usual Intravenous Access in Terminally Ill Cancer Patients: A Randomized Phase II Study.

PURPOSE: The purpose of this study was to investigate whether routine insertion of peripherally inserted central catheter (PICC) at admission to a hospice-palliative care (HPC) unit is acceptable in terms of safety and efficacy and whether it results in superior patient satisfaction compared to usual intravenous (IV) access. MATERIALS AND METHODS: Terminally ill cancer patients were randomly assigned to two arms: routine PICC access and usual IV access arm. The primary endpoint was IV maintenance success rate, defined as the rate of functional IV maintenance until the intended time (discharge, transfer, or death). RESULTS: A total of 66 terminally ill cancer patients were enrolled and randomized to study arms. Among them, 57 patients (routine PICC, 29; usual IV, 28) were analyzed. In the routine PICC arm, mean time to PICC was 0.84 days (range, 0 to 3 days), 27 patients maintained PICC with function until the intended time. In the usual IV arm, 11 patients maintained peripheral IV access until the intended time, and 15 patients underwent PICC insertion. The IV maintenance success rate in the routine PICC arm (27/29, 93.1%) was similar to that in the usual IV arm (26/28, 92.8%, p=0.958). Patient satisfaction at day 5 was better in the routine PICC arm (97%, 'a little comfort' or 'much comfort') compared with the usual IV arm (21%) (p <0.001). CONCLUSION: Routine PICC insertion in terminally ill cancer patients was comparable in safety and efficacy and resulted in superior satisfaction compared with usual IV access. Thus, routine PICC insertion could be considered at admission to the HPC unit.

Neutrophil-lymphocyte ratio predicts the therapeutic benefit of neoadjuvant transarterial chemoembolization in patients with resectable hepatocellular carcinoma.

BACKGROUND AND AIMS: All published meta-analyses failed to demonstrate that preoperative transarterial chemoembolization improves the clinical outcomes of patients with resectable hepatocellular carcinoma. The present study aimed to investigate the utility of systemic inflammatory cells as a tumor biology marker predicting therapeutic benefit of neoadjuvant transarterial chemoembolization in patients with resectable hepatocellular carcinoma. MATERIALS AND METHODS: We retrospectively investigated 441 hepatocellular carcinoma patients who underwent curative resection. Among 441 patients, 73 patients underwent preoperative transarterial chemoembolization, and 368 patients did not. We compared recurrence-free survival and overall survival between transarterial chemoembolization plus sequential resection group and resection only group. We analyzed whether pretreatment neutrophil-lymphocyte ratio demonstrates survival benefit in each groups. RESULTS: No significant difference was observed in recurrence-free or overall survival between both groups. In the transarterial chemoembolization plus sequential resection group, the 5-year overall survival in patients with high neutrophil-lymphocyte ratio (≥1.6) was significantly lower than that in patients with low neutrophil-lymphocyte ratio (78.4% and 100%, P = 0.027). High neutrophil-lymphocyte ratio was associated with vascular invasion (P = 0.033). CONCLUSION: Neutrophil-lymphocyte ratio can be considered as a predictive factor of long-term survival and used to identify patients with resectable hepatocellular carcinoma who benefit from neoadjuvant transarterial chemoembolization.