CUX1 modulates polarization of tumor-associated macrophages by antagonizing NF-κB signaling.

Many solid cancers including pancreatic ductal adenocarcinoma (PDAC) are characterized by an extensive stromal reaction that is accompanied by infiltrating tumor-associated macrophages (TAMs). The role of TAMs in malignant tumors is only partially understood. Previously, we identified the transcription factor CUX1 as an important mediator of tumor progression in PDAC. Interestingly, we found that CUX1 is highly expressed not only in tumor cells but also in TAMs. On the basis of these data, we aimed to elucidate the effects of CUX1 in TAMs in vitro and in vivo. We analyzed the effects of CUX1 on cytokine expression using overexpression and knockdown strategies. The cytokine regulation by CUX1 was further assessed by reporter assays, DNA pulldown experiments and chromatin-immunoprecipitation. CUX1 expression in TAMs was analyzed in human pancreatic cancer tissues and in a genetic mouse model. Immunohistochemical analysis revealed strong expression levels of CUX1 in a distinct subset of TAMs in human PDAC tissues. Furthermore, its expression increased during tumor progression in a genetic mouse model of PDAC. Profiling experiments showed that CUX1 downregulates several NF-κB-regulated chemokines such as CXCL10, which have been associated with M1 polarization and inhibition of angiogenesis and tumor progression. We could demonstrate that CUX1 interacts with NF-κB p65, leading to reduced binding of NF-κB p65 to the chemokine promoters. In addition, CUX1 reduces acetylation of NF-κB p65 at K310 by recruiting HDAC1. Functionally, CUX1 expression in TAMs antagonizes T-cell attraction and enhances angiogenesis in vitro. We identified CUX1 as an important modulator of the TAMs phenotype and function by modulating NF-κB-dependent cytokines.

Contrast-enhanced ultrasound (CEUS) in hepatic lymphoma: retrospective evaluation in 38 cases.

PURPOSE: Description of contrast-enhanced ultrasound (CEUS) patterns of hepatic lymphoma. MATERIALS AND METHODS: Over a period of 6 years and 1 month from January 2006 to January 2012, n = 38 patients with histological or clinically apparent hepatic lymphoma were studied by means of CEUS prior to B-mode imaging. RESULTS: Using B-mode imaging, lesions were hypoechoic in n = 37 (97.4 %) cases, while a focal lymphoma lesion was echo-rich in 1 case (2.6 %). For comparison, with CEUS, a hyperenhanced signal during the arterial phase was observed in n = 9 (23.7 %), an isoenhanced signal in n = 17 (44.7 %) and a hypoenhanced signal in n = 12 (31.6 %) cases. During the portal phase n = 2 (5.3 %) lesions were isoenhanced and n = 36 (94.7 %) were hypoenhanced followed by a hypoenhancement in n = 38 (100 %) cases in the late phase. CONCLUSION: Lymphomas of the liver can cause different contrast accumulation in the arterial phase of CEUS. Furthermore, a clear differentiation from other malignant liver lesions such as metastases is crucial as different contrast accumulation in the arterial phase of CEUS is observed. In the late phase, hepatic lymphomas lead to a hypoenhancement in CEUS, also known as a "wash-out" phenomenon. In conclusion, CEUS is helpful to differentiate hepatic lesions by means of evaluating the malignancy or benignancy. In this regard, the application of CEUS can help to find the right diagnosis. A final discrimination between malignant liver lesions, such as liver lymphomas, metastasis or HCC, remains impossible.

Percutaneous ultrasound-guided radiofrequency ablation (RFA) using saline-perfused (wet) needle electrodes for the treatment of hepatocellular carcinoma--long term experience.

PURPOSE: For many reasons, resection of hepatocellular cancer (HCC) is not feasible in most cases. Radiofrequency (RFA) ablation has proven to be an effective minimally invasive alternative. It has been shown in ex vivo and animal trials that needle applicators perfused with isotonic saline solution could be an effective approach to enlarging the coagulation zone. However, long term survival data for the treatment of HCC are not yet available. MATERIALS AND METHODS: 37 patients with a total of 64 histologically proven HCC with a maximum of 3 tumors of up to 6 cm and a contraindication to partial liver resection or orthotopic liver transplantation were treated with the Integra HiTT106 using wet monopolar single, wet bipolar double or wet triple needle electrodes. The mean HCC size was 37.7 mm (range 15 to 60 mm). Follow-up examinations were performed 2 days and 1, 3, 6, 9 months after RFA and every 6 months thereafter. The survival rate was calculated from the time of the first RFA session. RESULTS: 1, 2 and 5-year survival was 24/32 (75%), 14/31 (45%) and 3/21 (14%) overall; 18/19 (95%), 12/18 (67%) and 3/10 (30%) for HCC Child A; and 6/13 (46%), 2/13 (15%) and 0/11 (0%), for HCC Child B. Complete remission was achieved in 86.5 % of the patients (total: 32 out of 37, multi-needle 18 / 21, single needle 14 / 16). Distant recurrence occurred overall in 20 out of 37 patients (54%), including 9 of 21 treated with multiple needles (43% of patients) and 11 of the 16 patients treated with a single electrode (69%). The overall complication rate was 10.8%. Local recurrence was found for tumors measuring 3 cm-5 cm (n=28) in 7 out of 13 cases after single electrode RFA and in 1 out of 15 after multiple electrode treatment (significant, p=0.009). No significant difference between the single and multi-needle group was found for tumors >5 cm and <3 cm. CONCLUSION: RFA using multiple wet electrodes shows promise as an effective method for treating inoperable HCC especially in cases with well-preserved liver function. Multiple electrodes seem to be superior to single electrodes with respect to the local recurrence rate for tumors between 3 and 5 cm.