Pulmonary artery-bronchus fistula treated with coil embolization.

Bronchopulmonary arterial fistula consists of an abnormal connection between the bronchus and the vascular tree and is a rare but serious complication associated with a variety of lung interventions. We present a case of a 61-year-old female with a history of metastatic breast cancer treated with lumpectomy and radiation 20 years prior, who was found to have a fistula between the right pulmonary artery and the right mainstem bronchus. Our patient was treated endovascularly with coil embolization in the setting of massive hemoptysis flooding the trachea, which was successful in controlling the acute bleed, although care was withdrawn in the following days following a discussion with the family given the presence of advanced metastatic disease. This case illustrates the use of endovascular techniques to treat an actively bleeding bronchopulmonary arterial fistulae, including a review of the existing literature regarding the optimal endovascular management strategy. Although our patient did not achieve the best outcome, endovascular intervention with stent-placement or embolization can serve to temporarily halt blood flow through the fistula, stabilizing the patient and allowing for more radical therapy after improvement.

Classification System for Inferior Vena Cava (IVC) Appearance Following Percutaneous IVC Filter Retrieval.

OBJECTIVE: There is no classification system for describing inferior vena cava (IVC) injuries. The objective of this study was to develop a standardized grading system for venographic appearance of the IVC following percutaneous IVC filter retrieval. METHODS: A classification system for the appearance of the IVC on cavograms following percutaneous IVC filter removal was developed consisting of two grading elements; luminal characteristics and extravasation. Luminal narrowing from 0% up to 50% from any cause is grade 1; narrowing between 50 and 99% is grade 2; occlusion is grade 3; and avulsion is grade 4. Absence of extravasation is grade A, contained extravasation is grade B, and free extravasation is grade C. This system was then applied retrospectively to pre- and post-IVC filter retrieval cavograms performed at a single institution from October 2004 through February 2019. RESULTS: 546 retrieval attempts were identified with 509 (93.2%) filters successfully retrieved. 449 cases (88.2%) had both pre-retrieval and post-retrieval imaging appropriate for application of the proposed classification system. Inter-rater reliability was 0.972 for luminal characteristics, 0.967 for extravasation, and 0.969 overall. Consensus grading demonstrated a distribution of 97.3% grade 1, 1.3% grade 2, 1.3% grade 3, and 0.0% grade 4 for post-retrieval luminal characteristics. For extravasation classification, 96.4% of the cases were classified as grade A, 2.7% grade B, and 0.9% grade C. CONCLUSION: A classification system was developed for describing IVC appearance after IVC filter retrieval, and retrospectively validated using a single center dataset.

Palmar Warming for Radial Artery Vasodilation to Facilitate Transradial Access: A Randomized Controlled Trial.

PURPOSE: To investigate the efficacy of palmar warming to induce radial artery vasodilation. MATERIALS AND METHODS: After informed consent was obtained, healthy volunteers (n = 45) were randomized 2:1 in palmar warming and control groups, respectively, for this prospective, randomized, single-blind clinical trial (NCT03620383). The palmar warming group was given a warm, commercially available, air-activated heat pack (Kobayashi Consumer Products LLC, Dalton, Georgia) to hold in the left hand for palmar warming. The control group was given a deactivated version of the same heat pack. Left radial artery cross-sectional area (CSA) measurements were obtained at baseline and in 5-minute intervals up to 20 minutes in both groups. Differences in the trends of changes in the radial artery CSA between palmar warming and control groups were examined with the age- and sex-adjusted repeated measure analysis of variance. Propensity score-matched treatment effect analysis was conducted to quantify the effect of heat on radial artery CSA. RESULTS: The palmar warming group and the control group were significantly different in terms of subject sex (males/females: 7/23 and 10/5, respectively; P = .005) and baseline CSA (2.5±0.2 mm2 vs 3.2±0.3 mm2, respectively; P = .014). Radial artery CSA showed an increasing trend over time in the palmar warming group compared to a stable trend over time in the control group (P < .0001). Propensity score-matched comparison showed a 43.9% increase (95% confidence interval: 34.1%-53.8%) in CSA in the palmar warming group compared to the control group (P < .0001). CONCLUSIONS: The palmar warming technique is effective at dilating the radial artery and may be a beneficial technique to facilitate transradial access.

Association Between Sarcopenia and AFP Level in Patients Undergoing Liver Transplantation for Hepatocellular Carcinoma.

BACKGROUND: Sarcopenia is one of the most common complications of cirrhosis. Liver transplantation (LT) is the treatment of choice for patients with early-stage hepatocellular carcinoma (HCC) that are unsuitable for resection. METHODS: We performed a retrospective analysis of 163 patients transplanted at our institution with HCC from 1998 to 2016. Sarcopenia was diagnosed based on the skeletal muscle mass on computed tomography imaging using SliceOmatic 5.0 software at L3 level (≤52.4 cm2/m2 in males and ≤38.5 cm2/m2 in females). RESULTS: From the 163 patients who underwent LT for HCC, 119 had available computed tomography scan. From those, 61 were identified as sarcopenic by lumbar skeletal muscle index (LSMI), of which 53 patients were male (86.9%) with a median age of 59 y (56-64). The most common etiologies of cirrhosis were hepatitis C virus infection (55.7%) and alcohol liver disease (46.7%). A multivariable analysis was performed to find predictors of sarcopenia. Alpha-fetoprotein level >100 mg/dL (OR, 6.577; 95% CI: 1.370-51.464; P = 0.034) and gender (male) (OR, 5.878; 95% CI: 1.987-20.054; P = 0.002) were independently associated with the presence of sarcopenia in this cohort. Patients in the lowest quartile for LSMI had prolonged length of stay compared to the rest of the patients (P = 0.029). CONCLUSIONS: Alpha-fetoprotein level >100 mg/dL is associated with almost 6-fold increased risk of sarcopenia in patients with HCC undergoing LT. Patients in the lowest quartile of the LSMI are associated with 70% increased risk of prolonged length of stay in this cohort.

A prospective analysis of factors associated with decreased physical activity in patients with cirrhosis undergoing transplant evaluation.

BACKGROUND: Physical activity (PA) has been associated with improved recovery time after transplantation. Handgrip strength has been related to post-transplant outcomes. AIM: To evaluate predictors of PA and grip strength in patients with cirrhosis undergoing liver transplant evaluation. METHODS: Single-center, prospective analysis. RESULTS: One hundred patients were evaluated (54% male, mean age 53 ± 9). Common etiologies of liver disease were non-alcoholic steatohepatitis (27%), hepatitis C (22%) and alcoholic liver disease (21%). Mean model of end-stage liver disease (MELD) score was 13.5. Forty-one percent had a history of smoking. Ninety-three patients completed the International Physical Activity Questionnaire (IPAQ). The median total PA score was 33 metabolic equivalent (MET)-min/wk. The mean total grip strength was 62.1 ± 22 lb. Total grip strength was found to be an independent predictor of low-moderate PA (OR 4.7, 95% CI 1.4-16.2, p = 0.038), and smoking was the only significant factor associated with reduced grip strength (OR 3.4, 95% CI 1.4-8, p = 0.005). CONCLUSIONS: Patients with end-stage liver disease undergoing liver transplant evaluation have reduced total PA by IPAQ. Total grip strength was found to be a significant predictor of low-moderate PA in patients with cirrhosis. Smoking is a risk factor for reduced grip strength, an important indicator of muscle wasting in cirrhotics.

Targeting the Wnt/ß-catenin signaling pathway in liver cancer stem cells and hepatocellular carcinoma cell lines with FH535.

Activation of the Wnt/ß-catenin pathway has been observed in at least 1/3 of hepatocellular carcinomas (HCC), and a significant number of these have mutations in the ß-catenin gene. Therefore, effective inhibition of this pathway could provide a novel method to treat HCC. The purposed of this study was to determine whether FH535, which was previously shown to block the ß-catenin pathway, could inhibit ß-catenin activation of target genes and inhibit proliferation of Liver Cancer Stem Cells (LCSC) and HCC cell lines. Using ß-catenin responsive reporter genes, our data indicates that FH535 can inhibit target gene activation by endogenous and exogenously expressed ß-catenin, including the constitutively active form of ß-catenin that contains a Serine37Alanine mutation. Our data also indicate that proliferation of LCSC and HCC lines is inhibited by FH535 in a dose-dependent manner, and that this correlates with a decrease in the percentage of cells in S phase. Finally, we also show that expression of two well-characterized targets of ß-catenin, Cyclin D1 and Survivin, is reduced by FH535. Taken together, this data indicates that FH535 has potential therapeutic value in treatment of liver cancer. Importantly, these results suggest that this therapy may be effective at several levels by targeting both HCC and LCSC.

Synergistic inhibition of HCC and liver cancer stem cell proliferation by targeting RAS/RAF/MAPK and WNT/ß-catenin pathways.

BACKGROUND/AIM: The aim of this study is to find synergistic effect using FH535 and sorafenib by targeting the RAS/RAF/MAPK and WNT/ß-catenin pathways. MATERIALS AND METHODS: 3H-Thymidine incorporation assays were performed to address Huh7 and liver cancer stem cell (LCSC) inhibition using FH535 and sorafenib, alone and in combination. Calcusyn analysis was used to calculate the combination index (CI). A western blot assay was performed to check for potential targets. RESULTS: FH535 and sorafenib caused inhibition of Huh7 and LCSC. Combination therapy was significantly better than monotherapy in inhibition of HuH7. Combination with sorafenib and FH535 was found to be synergistic in inhibition of LCSC with a CI of less than 1. The western blot assay demonstrated enhanced cleaved poly (ADP-ribose) polymerase (PARP) and inhibition of cyclin D1, B-cell lymphoma 2 (Bcl2), survivin and cellular myelocytomatosis oncogene (c-MYC). CONCLUSION: FH535 and sorafenib combination produced synergistic effect on inhibition of HCC and LCSC. Our study demonstrated that FH535 can induce apoptosis in these two different hepatocellular carcinoma (HCC) cell lines.

Molecular therapies in hepatocellular carcinoma: what can we target?

Numerous signaling pathways, such as Ras/Raf/MAPK, have been implicated in hepatic carcinogenesis. There are at least 35 combination therapy studies for advanced stage hepatocellular carcinoma (HCC) ongoing, and numerous reagents are being tested targeting novel signaling cascades. The management of HCC has changed substantially in recent times, and the successful development of sorafenib has prompted further expansion on molecular targeted therapies to potentially inhibit different pathways in hepatocarcinogenesis.

PKI-587 and sorafenib alone and in combination on inhibition of liver cancer stem cell proliferation.

BACKGROUND: Deregulated Ras/Raf/mitogen-activated protein kinase and PI3 K/AKT/mTOR signaling pathways are significant in hepatocellular carcinoma proliferation (HCC). In this study we evaluated differences in the antiproliferative effect of dual PI3 K/Akt/mTOR and Ras/Raf/mitogen-activated protein kinase inhibition of non liver cancer stem cell lines (PLC and HuH7) and liver cancer stem cell (LCSC) lines (CD133, CD44, CD24, and aldehyde dehydrogenase 1-positive cells). MATERIALS AND METHODS: Flow cytometry was performed on the resulting tumors to identify the LCSC markers CD133, CD44, CD24, and aldehyde dehydrogenase 1. Methylthiazol tetrazolium assay was used to assess cellular proliferation. Finally, a Western blot assay was used to evaluate for inhibition of specific enzymes in these two signaling pathways. RESULTS: Using flow cytometry, we found that LCSC contain 64.4% CD133 + cells, 83.2% CD44 + cells, and 96.4% CD24 + cells. PKI-587 and sorafenib caused inhibiton of LCSC and HCC cell proliferation. PLC cells were more sensitive to PKI-587 than LCSC or Huh7 (P < 0.001). Interestingly, HuH7 cells were more sensitive to sorafenib than LCSC or PLC cells. Additionally, combination therapy with PKI-587 and sorafenib caused significantly more inhibition than monotherapy in HuH7, PLC, and LCSC. Using the methylthiazol tetrazolium assay, we found that the LCSC proliferation was inhibited with sorafenib monotherapy 39% at 5 µM (P < 0.001; n = 12) and 67% by PKI-587 at 0.1 µM (P = 0.002, n = 12) compared with control. The combination of PKI-587 and sorafenib, however, synergistically inhibited LCSC proliferation by 86% (P = 0.002; n = 12). CONCLUSIONS: LCSC (CD133+, CD44+, CD24+) were able to develop very aggressive tumors with low cell concentrations at 4 to 6 wk. Cells CD133+, CD44+, CD24+, which demonstrated at least moderate resistance to therapy in vitro. The combination of PKI-587 and sorafenib was better than either drug alone at inhibiting of LCSC and on HCC cell proliferation.

The role of bridging therapy in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is the most common primary malignancy of the liver accounting for 7% of all cancers worldwide. Most cases of HCC develop within an established background of chronic liver disease. For that reason, liver resection is only possible in selected patients. Liver transplantation has become the treatment of choice in patients with HCC, end-stage liver disease, and significant portal hypertension. Shortage of organ donors has resulted in overall increase of waiting list time with increased risk of dropout due to tumor progression. Neoadjuvant therapies have emerged as an alternative to control tumor growth in patients while waiting. The aim of this study is to review the literature on the role of bridging therapy and downstaging prior to liver transplantation in patients with HCC. We are also presenting our single-center experience of 96 patients undergoing transplantation for HCC with and without bridging therapy.