Repeated SBRT for in- and out-of-field recurrences in the liver.

PURPOSE: To evaluate the feasibility and toxicity profile of repeated stereotactic body radiotherapy (SBRT) for recurrent primary or secondary liver tumors. METHODS: Consecutive patients with primary (hepatocellular carcinoma [HCC] or cholangiocarcinoma [CCC]) or secondary liver cancer (LM), with intrahepatic recurrence or progression after SBRT, underwent re-SBRT in 3 to 12 fractions with a median time of 15 (range 2-66) months between treatments. RESULTS: In all, 24 patients which were previously treated with SBRT (30 lesions) were retreated with SBRT for "in- and out-of-field" recurrences (2nd SBRT: n = 28, 3rd SBRT: n = 2). The median follow-up after re-irradiation was 14 months. The median prescribed dose for the first SBRT was 46.5 (range 33-66 Gy, EQD210 = 70.5) Gy and 48 (range 27-66 Gy, EQD210 = 71) Gy for the re-SBRT. The median mean liver dose (Dmean, liver) was 6 Gy (range 1-25, EQD22 = 7 Gy) for the first SBRT and 10 Gy (range 1-63 Gy, EQD22 = 9 Gy) for the re-SBRT. Of the 30 re-irradiated lesions 6 were re-irradiated in-field resulting in a median EQD22, maximum of 359 (range 120-500) Gy for both treatments, with an α/ß = 2 to account for liver parenchyma. Treatment was well tolerated. Two patients with stent placement before SBRT developed cholangitis 4 and 14 months after re-SBRT. There were no elevations of the serum liver parameters after re-SBRT. One patient developed a grade 3 gastrointestinal bleeding. There was no radiation induced liver disease (RILD) observed. CONCLUSIONS: Repeated liver SBRT is feasible, without excessive liver toxicity, when there is no considerable overlapping with pre-irradiated portions of the stomach or bowel and enough time for the liver to regenerate.

The role of albumin-bilirubin grade and inflammation-based index in patients with hepatocellular carcinoma treated with stereotactic body radiotherapy.

PURPOSE: We evaluated the prognostic accuracy of the albumin-bilirubin (ALBI) grade and the inflammation-based index (IBI) in estimating overall survival (OS) and toxicity in patients with hepatocellular carcinoma (HCC) treated with stereotactic body radiotherapy (SBRT). MATERIALS AND METHODS: Forty patients with 47 HCC lesions with a Barcelona Clinic Liver Cancer (BCLC) classification stage B or C were treated with SBRT in 3-12 fractions. The ALBI grade and the IBI were calculated at different time points (baseline, during, at the end of treatment and at follow-up) and compared with the Child-Pugh (CP) score as well as other patient- and treatment-related parameters, concerning OS and toxicity. RESULTS: The median follow-up was 14.3 months for patients alive. The median OS from SBRT was 10 (95% confidence interval 8.3-11.6) months. The local control at 1 year was 79%. A lower IBI during treatment was associated with better OS (p = 0.034) but not CP and ALBI. Higher C­reactive protein levels as well as higher alpha-fetoprotein concentrations correlated with worse survival (p = 0.001). Both higher ALBI (p = 0.02) and CTP (p = 0.001) at baseline correlated with a higher incidence of acute and late toxicities (CTC ≥2). Neither the mean radiation dose to the liver nor the dose to 700 cc of the liver correlated with the occurrence of toxicities. CONCLUSIONS: In this analysis, a higher ALBI grade as well as a higher CP were predictors of higher incidence of toxicity, whereas a lower IBI during treatment correlated with a better OS. These results should be further evaluated in prospective studies.

Comparison of local tumor control in patients with HCC treated with SBRT or TACE: a propensity score analysis.

BACKGROUND: As stereotactic body radiation therapy (SBRT) has shown to be effective and safe in patients with hepatocellular carcinoma (HCC), the aim of our propensity score matched analysis was to evaluate the efficacy of SBRT in comparison to transarterial chemoembolization (TACE) in intermediate and advanced HCC. METHODS: Patients treated with TACE (n = 367) and patients allocated to SBRT (n = 35) were enrolled in this study. Propensity score matching was performed to adjust for differences in baseline and tumor characteristics of TACE and SBRT patients. Local tumor control (LC) 1 year after treatment, overall survival (OS) and 1-year mortality were assessed. RESULTS: Patients treated with SBRT have received more prior HCC treatments compared to TACE patients. The LC 1 year after treatment in the unmatched cohort was 74.4% for TACE patients compared to 84.8% in the SBRT group. Patients treated with TACE showed significantly improved OS (17.0 months vs. 9.0 months, p = 0.016). After propensity score matching, the LC in the TACE (n = 70) and SBRT (n = 35) group was comparable (82.9% vs. 84.8%, p = 0.805) and OS did not differ significantly in both groups. CONCLUSIONS: SBRT after prior HCC therapy in selected patients shows comparable LC at 1 year, OS and 1-year mortality compared to patients treated with TACE.

Survival benefit of transarterial chemoembolization in patients with metastatic hepatocellular carcinoma: a single center experience.

BACKGROUND: As prognosis of patients with metastatic hepatocellular carcinoma (HCC) is mainly determined by intrahepatic HCC progression, local treatment with TACE may result in improved OS, although it is not recommended. The purpose of this study was to analyze retrospectively the efficacy of TACE and its impact on OS in patients with metastatic hepatocellular carcinoma (HCC). METHODS: Two hundred and fifteen patients with metastatic HCC who were treated at our Liver Center between 2003 and 2014 were included in this retrospective analysis. Medical records, laboratory parameters and imaging studies were analyzed. Treatment of metastatic HCC and OS were assessed RESULTS: One hundred and two patients (47.4%) did not receive any HCC specific treatment while 48 patients (22.3%) were treated with sorafenib, 42 patients (19.5%) with TACE and 23 patients (10.7%) received treatment with TACE and sorafenib in combination. Survival analyses and Cox regression models revealed that TACE and a combination therapy of TACE and sorafenib were significant prognostic factors in metastatic HCC. However, further analyses revealed that there was no additional prognostic effect of adding sorafenib to TACE treatment in this patient cohort. CONCLUSIONS: In metastatic HCC, treatment of intrahepatic tumor by TACE may be associated with improved survival. These results support the prognostic importance of treating intrahepatic HCC even in patients with metastatic disease. Therefore, we suggest evaluating the technical feasibility of TACE in all metastatic patients.

Inferior mesenteric artery diameter and number of patent lumbar arteries as factors associated with significant type 2 endoleak after infrarenal endovascular aneurysm repair.

OBJECTIVES: Our goal was to identify the inferior mesenteric artery diameter and number of patent lumbar arteries causing a significant type 2 endoleak to develop after infrarenal endovascular aneurysm repair. MATERIAL AND METHODS: Included were patients who underwent infrarenal endovascular aneurysm repair between April 2002 and January 2017. Patients with an aneurysm involving the iliac arteries were excluded. Significant type 2 endoleak was defined as a type 2 endoleak observed after infrarenal endovascular aneurysm repair and accompanied by abdominal aneurysm growth of at least 5 mm during that time. RESULTS: A total of 277 patients were included. Mean follow-up was 38.9 (standard deviation 121.6) months. Immediately after infrarenal endovascular aneurysm repair, type 2 endoleaks occurred in 55 patients (20%), resolving spontaneously in 2 patients 6 months after infrarenal endovascular aneurysm repair. Thirty (10.8%) patients revealed a significant type 2 endoleak with aneurysm sack enlargement > 5 mm during follow-up, for which inferior mesenteric artery or lumbar artery coiling was performed. Mean time for coiling after primary infrarenal endovascular aneurysm repair was 25.4 (standard deviation 19.10) months. Twenty-three patients (8.3%) showed a non-significant type 2 endoleak during follow-up (no aneurysm sack enlargement). We found that the inferior mesenteric artery diameter and number of patent lumbar arteries were factors associated with a significant type 2 endoleak (odds ratio 1.755, P = 0.001; odds ratio 1.717, P < 0.001, respectively). Prior to endovascular aneurysm repair, the inferior mesenteric artery was patent in 212 (76.5%) patients; its median diameter measured 3 (0.5-3.8) mm. The median number of patent lumbar arteries was 3 (2-4). According to our receiver operating characteristic curve analysis, an inferior mesenteric artery diameter ≥3 mm (sensitivity 93.3%, specificity 65%) and ≥3 patent lumbar arteries (sensitivity 87.5%, specificity 43.6%) proved to be optimal cut-off values related to developing a significant type 2 endoleak. We therefore propose a composite score for the development of a significant type 2 endoleak [(inferior mesenteric artery diameter + patent lumbar arteries)/2]. CONCLUSIONS: Patients in whom the diameter of the inferior mesenteric artery is ≥ 3 mm and with ≥ 3 patent lumbar arteries carry a higher risk of developing significant type 2 endoleak after infrarenal endovascular aneurysm repair.

Management and endovascular therapy of ureteroarterial fistulas: experience from a single center and review of the literature.

BACKGROUND: Ureteroarterial fistula (UAF) is a rare but potentially life threatening disease. The aim of this study was to evaluate the outcome of endovascular therapy for UAF treatment. METHODS: This retrospective case series evaluates a single center experience of percutaneous stent graft (SG) angioplasty and/or coil embolization for UAF. Patient follow-up included technical and early clinical success, complications and revisional procedures. We also conducted a systematic review of the literature reporting on endovascular UAF management. RESULTS: We identified 17 UAF in 16 patients (12 male, 4 female, mean age 69.8 ± 11.3 years) who underwent endovascular UAF therapy at our tertiary hospital. All patients presented with hematuria. 5/17 (29.4%) presented with flank pain, in 7 (41.2%) cases patients were in hypovolemic shock. Risk factors of UAF included chronic indwelling ureteral stents in all fistulas, major pelvic surgery in 13 cases (76.5%). In 6 cases (35.3%) SG were placed from the common iliac artery (CIA) to the external iliac artery (EIA) following coil embolization of the proximal internal iliac artery (IIA). SG placement without previous coil embolization was performed in 10 fistulas (58.8%). In one case only coil embolization of the IIA was performed. Mean follow-up was 654 (range: 1-3269) days. All procedures were technically successful and no procedure related deaths occurred during follow-up. During the initial hospital stay hematuria disappeared in 14/17 cases (82.4%). Overall, four patients suffered recurrent hematuria, which in three cases resolved after a secondary intervention. One recurrent UAF related death occurred during follow-up 229 days after initial treatment. A total of 152 UAF cases were additionally analyzed from our systematic literature review: SG placement with or without embolization was performed in 140 cases (92.1%) while embolization alone was done in 12 cases (7.9%). Complications included UAF recurrence (18/152, 11.8%), SG thrombosis (7/140, 5%), and SG infections (5/140, 3.6%) with an overall complications rate of 13.8%. Five patients died due to UAF (3.3%). CONCLUSION: Endovascular therapy offers high technical success rates and rapid bleeding control of UAF. Severe complications like SG occlusions or SG infections are rare but significant. Antibiotic treatment and single anti-platelet therapy improve SG durability as well as close and long follow-up to timely perform repeated endovascular or surgical treatment if necessary. EVIDENCE-BASED MEDICINE: Level 4, case series.

Over-the-scope clip versus transcatheter arterial embolization for refractory peptic ulcer bleeding-A propensity score matched analysis.

BACKGROUND: Transcatheter arterial embolization (TAE) or surgery are standard treatment of peptic ulcer bleeding (PUB) refractory to endoscopic hemostasis. Over-the-scope clips (OTSC) have shown superiority to standard endoscopic treatment. OBJECTIVE: To compare OTSC treatment to TAE in refractory peptic ulcer bleeding. PATIENTS AND METHODS: In this retrospective, multicenter study, 128 patients treated with OTSC (n = 66) or TAE (n = 62) for refractory PUB between 2009 and 2019 in four academic centers were analyzed. Primary endpoint was clinical success (hemostasis + no rebleeding within 7 days). Secondary endpoints were adverse events, length of ICU stay, and mortality. Propensity score matching was performed to adjust for differences in baseline characteristics. RESULTS: Patients characteristics were similar in both groups but ulcers in the TAE group were larger, more often located in the duodenal bulb (85.5% vs. 65.2%; p = 0.014), and that the proportion of Forrest Ia bleedings was higher (38.7% vs. 19.7%; p = 0.018). Clinical success was comparable in both groups (74.2% vs. 59.7%; p = 0.092). Stay on the intensive care unit (ICU) was significantly longer in the TAE group (mean 8.0 vs. 4.7 days; p = 0.002). Serious adverse events after re-therapy (12.9% vs. 1.5%; p = 0.042) and in-hospital mortality were significantly higher in the TAE group (9.1 vs. 22.6%, OR 2.92 [95% CI 1.04-8.16]; p = 0.05). After propensity score matching, the differences found regarding ICU stay (4.9± 5.9 and 9.2 ± 11.2; p = 0.009) and in-hospital mortality (5% vs. 22.5%; OR 5.52 [95% CI: 1.11-27.43]; p = 0.048) stayed significant. CONCLUSIONS: OTSC treatment for refractory PUB was superior to TAE in terms of ICU stay and in-hospital mortality.

Efficacy of Stereotactic Body Radiotherapy in Patients With Hepatocellular Carcinoma Not Suitable for Transarterial Chemoembolization (HERACLES: HEpatocellular Carcinoma Stereotactic RAdiotherapy CLinical Efficacy Study).

The aim of this prospective observational trial was to evaluate the efficacy, toxicity and quality of life after stereotactic body radiation therapy (SBRT) in patients with hepatocellular carcinoma (HCC) and to assess the results of this treatment in comparison to trans-arterial chemoembolization (TACE). Patients with HCC, treated with TACE or SBRT, over a period of 12 months, enrolled in the study. The primary endpoint was feasibility; secondary endpoints were toxicity, quality of life (QOL), local progression (LP) and overall survival (OS). Between 06/2016 and 06/2017, 19 patients received TACE and 20 SBRT, 2 of whom were excluded due to progression. The median follow-up was 31 months. The QOL remained stable before and after treatment and was comparable in both treatment groups. Five patients developed grade ≥ 3 toxicities in the TACE group and 3 in the SBRT group. The cumulative incidence of LP after 1-, 2- and 3-years was 6, 6, 6% in the SBRT group and 28, 39, and 65% in the TACE group (p = 0.02). The 1- and 2- years OS rates were 84% and 47% in the TACE group and 44% and 39% in the SBRT group (p = 0.20). In conclusion, SBRT is a well-tolerated local treatment with a high local control rates and can be safely delivered, while preserving the QOL of HCC patients.

Adjuvant Transjugular Variceal Occlusion at Creation of a Transjugular Intrahepatic Portosystemic Shunt (TIPS): Efficacy and Risks of Bucrylate Embolization.

Adjuvant embolization of varices may reduce rebleeding in patients with a transjugular intrahepatic portosystemic shunt (TIPS). The aim of this study was to investigate the efficacy and the risks of adjuvant variceal embolization at TIPS implantation using bucrylate. PATIENTS AND METHODS: The retrospective study evaluated 104 of 237 cirrhotic patients with TIPS for variceal bleeding who received adjuvant bucrylate embolization. For TIPS creation, bare stents were used in 35 patients (33.7%) and covered stents in 69 patients (66.3%) patients. Isolated gastric varices were seen in 10 patients (9.6%). RESULTS: Six patients (5.8%) rebled during a median follow-up time of 26 months (1-57 months). Rebleeding occurred in 14% (5/35) of patients with a bare stent but only in 1.4% (1/69) of patients with a covered stent. The 1- and 2-year rebleeding rates of all patients were 0.9 and 2.9% and of patients receiving a bare stent were 2.9 and 8.6%, respectively. Bucrylate migration was seen in 13 patients (12.5%). In 9 of these patients (8.7%), asymptomatic lung embolization occurred. This was rare in patients with esophageal varices (3.1%) but frequent (60%) in patients with isolated gastric varices and a spontaneous splenorenal shunt. CONCLUSIONS: Our results suggest that adjuvant embolization using bucrylate is effective and delays variceal rebleeding. The general use of covered stents, however, alleviates the utility of adjuvant bucrylate embolization which may be restricted to patients with a high risk of rebleeding indicated by large varices, active, acute or recent variceal bleeding and advanced cirrhosis. Bucrylate should not be used in isolated gastric varices because it bears a high risk of migration into the lungs.

Kidney embolization induces prompt organ response in a 86-year-old patient with MGRS-related AL-amyloidosis.

Despite substantial improvements following the introduction of novel agents and antibodies, amyloid light-chain (AL)-amyloidosis still carries a grim prognosis. Here, we report on the case of a severely frail 86-year-old patient suffering from monoclonal gammopathy of renal significance (MGRS)-associated AL-amyloidosis with a diuretic-refractory nephrotic syndrome. In this patient, treatment with bortezomib-dexamethasone effectively induced a serological response, but was unfortunately poorly tolerated and failed to promote renal recovery fast enough to prevent secondary complications. Facing ongoing nephrotic syndrome, we performed unilateral kidney embolization and observed a substantial improvement of hypoalbuminemia accompanied by a significant gain in overall quality of life despite the necessity for thrice weekly dialysis. It can be concluded that systemic drugs in MGRS typically do not lead to instantaneous organ recovery but may initially rather be associated with substantial treatment-related morbidity. In this setting, unilateral renal artery embolization is effective to treat nephrotic syndrome and its secondary complications. The risk of potentially adverse effects, including post-embolization syndrome, can be minimized by unilateral embolization, still noting that also one-sided renal ablation has to be balanced against the requirement for life-long renal replacement therapy. Prospective controlled trials in a more comprehensive cohort will be needed to estimate the overall benefit of kidney embolization relative to novel agent therapies in frail patients with MGRS-related AL-amyloidosis.

A role for the neurotrophin receptor TrkB on maturing dendritic cells.

BACKGROUND: Neurotrophins are involved in neuroimmune interactions. However, the expression and role of neurotrophin receptors on dendritic cells have not been systematically studied. METHODS: The neurotrophin receptors p75NTR, TrkA, TrkB and TrkC were analyzed on immature and mature Human Monocyte-derived Dendritic Cells (HMDCs) using flow cytometry. In addition, we compared the impact of five different maturing protocols on the expression of neurotrophin receptors on HMDCs. Finally, the effect of neurotrophins on surface molecule expression and the survival of HMDCs was investigated. RESULTS: There was a low expression of p75NTR, TrkA and TrkB on immature HMDCs. HMDCs at different maturation stages did not show a significantly different expression of TrkA, as compared to immature HMDCs. By contrast, there was an upregulation of TrkB on suboptimally, but not optimally matured HMDC. In addition, there was a non-significant trend to a parallel increase of p75NTR expression on these cells. Functional experiments with maturing HMDCs revealed that both ligands of the TrkB receptor, Brain-derived neurotrophic factor (BDNF) and Neurotrophin 4 (NT-4), significantly increased the expression of markers of antigen presentation (HLA-DR and CD80) and the survival of maturing HMDCs. CONCLUSION: These data suggest that the TrkB ligands BDNF and NT-4 can directly influence human dendritic cells during their maturation.

Excellent local control and tolerance profile after stereotactic body radiotherapy of advanced hepatocellular carcinoma.

BACKGROUND: To evaluate the efficacy and toxicity of stereotactic body radiotherapy (SBRT) in the treatment of advanced hepatocellular carcinoma (HCC). MATERIAL AND METHODS: Patients with large HCCs (median diameter 7 cm, IQR 5-10 cm) with a Child-Turcotte-Pugh (CTP) score A (60%) or B (40%) and Barcelona-Clinic Liver Cancer (BCLC) classification stage B or C were treated with 3 to 12 fractions to allow personalized treatment according to the size of the lesions and the proximity of the lesions to the organs at risk aiming to give high biologically equivalent doses assuming an α/ß ratio of 10 Gy for HCC. Primary end points were in-field local control and toxicity assessment. RESULTS: Forty seven patients with 64 lesions were treated with SBRT (median 45 Gy in 3-12 fractions) with a median follow up for patients alive of 19 months. The median biological effective dose was 76 Gy (IQR 62-86 Gy). Tumor vascular thrombosis was present in 28% and an underlying liver disease in 87% (hepatitis B or C in 21%, alcohol related in 51%, nonalcoholic steatohepatitis in 13% of the patients, primary biliary cirrhosis 2%). Eighty three percent received prior and in most cases multiple therapies. Local control at 1 year was 77%. The median overall survival from the start of SBRT was 9 months (95% CI 7.7-10.3). Gastrointestinal toxicities grade ≥ 2 were observed in 3 (6.4%) patients. An increase in CTP score without disease progression was observed in 5 patients, of whom one patient developed a radiation induced liver disease. One patient died due to liver failure 4 months after treatment. CONCLUSION: SBRT is an effective local ablative therapy which leads to high local control rates with moderate toxicity for selected patients with large tumors.

[How to do: transarterial chemoembolization (TACE)]. / Transarterielle Chemoembolisation (TACE).

Transarterial Chemoembolization (TACE) is the standard procedure for intermediate stage hepatocellular carcinoma (HCC). TACE combines local chemotherapy with embolization of the arterially hypervascularisated HCC. In this article we present indication, contraindication, technical background, practical approach and side effect of TACE.