Peter E. Huppert

Expression of hypoxia-inducible genes in tumor cells

Abstract Tumor tissue oxygenation impacts on proliferation of cancer cells and their sensitivity towards radio- and chemotherapy. Under low oxygen, mammalian cells show an adaptive response that leads to the induction of a number of genes with well-defined roles in oxygen supply and energy maintenance, e.g. genes encoding enzymes of the glycolytic pathway. The hypoxia-inducible factor 1 (HIF-1), a transcription factor consisting of the two proteins HIF-1α and HIF-1β, plays a major role in the pleiotropic response observed under low oxygen. We have determined, by Northern analysis, the mRNA levels of HIF-1α and of two glycolytic enzymes known to be transcriptionally activated by HIF-1, namely phosphoglycerate kinase 1 (PGK 1) and pyruvate kinase M2 (PKM2), in different hepatoma cell lines and in mouse and human tissues. Hypoxic treatment of various mouse and human hepatoma cell lines led to the expected increase in the amount of PGK1 and PKM2 mRNA, while HIF-1α mRNA levels were not significantly elevated. Analysis of mouse liver tumors demonstrated no tumor-specific increases in HIF-1α or PGK1 mRNA levels. In five of eight human colorectal cancers investigated, PGK1 and PKM2 mRNA levels were increased in comparison to the corresponding normal tissues, while HIF-1α mRNA levels were not significantly changed. The majority of the colorectal cancers demonstrated p53 immunoreactivity, presumably due to mutation of the gene; there was, however, no correlation between the p53 staining pattern and mRNA expression levels of glycolytic enzymes.

Embolization of renal vascular lesions: Clinical experience with microcoils and tracker catheters

After biopsy (n=6) and nephrostomy (n=1) of three native and four transplanted kidneys, gross hematuria, hypertension, and deterioration of function necessitated performance of transarterial embolization. Angiography revealed five arteriovenous fistulas (AVFs), one pseudoaneurysm, and one arteriocaliceal fistula. Superselective catheterization was accomplished using 5 Fr standard diagnostic catheters and 3 Fr coaxial Tracker catheters. Four of five AVFs were embolized successfully by inserting unfibered (2 patients) and fibered (2 patients) platinum coils (diameters 2 mm and 4 mm, respectively). For one AVF, additional injection of butylcyanoacrylate was necessary. The pseudoaneurysm was embolized successfully by such injection, and the arteriocaliceal fistula was occluded using one unfibered 2-mm coil. Embolization stopped the bleeding in all patients. One week after treatment, renal function was improved in 5 patients and remained unaffected in 2. Superselective embolization using Tracker catheters and fibered microcoils is an effective, safe treatment of renal vascular lesions.

Transarterial chemoembolization of liver metastases in patients with uveal melanoma

Metastases from uveal melanoma are often confined to the liver. Palliative hepatic chemoembolization has been considered to be a reasonable treatment approach. We enrolled 14 patients with hepatic metastases from uveal melanoma into a pilot trial of transarterial chemoembolization (TACE). All patients received additional systemic immuno-chemotherapy or best supportive care. In 31 procedures 100mg/m(2) of cisplatine was continuously infused by means of a power injector preceding embolization by manual injection of polyvinyl alcohol particles. In three procedures cisplatine was replaced by 200mg/m(2) carboplatine because of increased serum creatinine levels. Tumor response was evaluated using RECIST criteria. Fourteen patients received 34 TACEs (mean: 2.4 treatments). Eight patients (57%) achieved partial response (PR), four patients (29%) had stable disease and two patients (14%) tumor progression. Median time to progression was 8.5 months (5-35 months). Median survival after first TACE was 14.5 months in responders compared to 10 months in non-responders (p=0.18, not significant) and 11.5 months (3-69 months) in all patients. In seven patients with metastases occupying less than 25% of liver volume median survival was 17 months compared to 11 months in seven patients with tumor involvement of more than 25% (p=0.02) with partial response rate of 86% and 29%, respectively. TACE of liver metastases from uveal melanoma is well tolerated and may prolong survival in patients with limited tumor extension.

Non-operative management of arterial liver hemorrhages

Abstract. A retrospective evaluation of embolotherapy in patients with arterial liver hemorrhages was carried out. Twenty-six patients, ranging in age from 10 days to 77 years with active arterial liver hemorrhages, underwent non-surgical embolotherapy. Bleeding was attributed to trauma (n = 21), tumor (n = 3), pancreatitis (n = 1), or unknown cause (n = 1). Twenty-nine embolizations were performed via a transfemoral (n = 26) or biliary (n = 2) approach. One bare Wallstent was placed into the common hepatic artery via to an axillary route to cover a false aneurysm due to pancreatitis. Treatment was controlled in 4 patients by cholangioscopy (n = 2) or by intravascular ultrasound (n = 2). Prior surgery had failed in 3 patients. Intervention controlled the hemorrhage in 24 of 26 (92 %) patients within 24 h. Embolotherapy failed in 1 patient with pancreatic carcinoma and occlusion of the portal vein. In 1 patient with an aneurysm of the hepatic artery treated by Wallstent insertion, total occlusion was not achieved in the following days, as demonstrated by CT and angiography. However, colour Doppler flow examination showed no flow in the aneurysm 6 months later. Complications were one liver abscess, treated successfully by percutaneous drainage for 10 days, and one gallbladder necrosis after superselective embolization of the cystic artery. Embolization is a effective tool with a low complication rate in the treatment of liver artery hemorrhage, even in patients in whom surgery has failed.

Transjugular intrahepatic portosystemic shunts in children with biliary atresia.

Purpose: We retrospectively evaluated the technical and long-term clinical results of transjugular intrahepatic portosystemic shunts (TIPS) in children with portal hypertension and biliary atresia (BA). Methods: Nine children with BA and recurrent bleeding from esophagogastric and/or intestinal varices were treated by TIPS at the age of 34–156 months and followed-up in two centers. Different types of stents were used. Results: Shunt insertion succeeded in all patients, but in two a second procedure was necessary. Seven procedures lasted more than 3 hr, mainly due to difficult portal vein puncture. Variceal bleeding ceased in all patients; however, 16 reinterventions were performed in eight patients for clinical reasons (n = 11) and sonographically suspected restenosis (n = 5). Four patients underwent successful liver transplantation 4–51 months after TIPS and five are in good clinical conditions 64–75 months after TIPS. Conclusions: TIPS in children with BA is technically difficult, mainly due to periportal fibrosis and small portal veins. Frequency of reinterventions seems to be higher compared with adults.

[MRI-guided percutaneous radiofrequency ablation of hepatic neoplasms--first technical and clinical experiences].

Purpose: To evaluate the safety and efficacy of MR-guided radiofrequency ablation (RFA) of hepatic neoplasms. Material and Methods: 16 hepatic neoplasms (1.3-3.0 cm in diameter) in 11 patients were treated by 22 percutaneous RFA sessions during a prospective study. 16 G, MR-compatible cooled-tip electrodes with active lengths of 2 cm and 3 cm, respectively, were placed under MR-guidance in an open 0.2 Tesla MR system (Magnetom Open, Siemens, Erlangen) using fast T 1 -weighted sequences. Pretreatment studies, evaluation of tumor necrosis (one week after last RFA), and further follow-up studies every 3 months were performed using 1.5 Tesla MR systems. Results: The mean procedure time was 2.8 (1.5-3.3)h. Complications related to percutaneous treatment were not encountered. 14 of 16 neoplasms (87%) showed no CM enhancement during MRI after the last RFA and were judged to be completely necrotic. In 11 tumors one treatment session was necessary, in 4 tumors two and in one tumor three. Follow-up studies revealed persistent complete necrosis in 13 of 14 (93%) tumors during a period of 3 - 18 (median: 11.8) months. In 5 patients new intrahepatic tumors developed that were not suitable for further RFA treatment because of their number, size and location, conclusion: MR-guided RFA using single cooled tip electrodes is safe and technically effective for treatment of hepatic neoplasms up to 3 cm in size, however further improvements are necessary.

Evaluation of K-Space Segmented Cine Sequences for Fast Functional Cardiac Imaging

RATIONALE AND OBJECTIVES In functional cardiac magnetic resonance imaging, reduction of measuring time is very important for many patients who are not able to rest motionless for long-lasting examinations. In this study, the image quality of sequences with k-space segmented data recording was compared with conventional gradient-echo sequences for cine imaging with flow compensation in applications on patients with normal and reduced ejection fractions. METHODS Thirty-one subjects (4 volunteers and 27 patients with cardiac diseases) were examined using different techniques for cine imaging of the left and right ventricles. The ejection fraction in the patients was calculated based on images of a conventional two-dimensional gradient-echo technique using a biplane ellipsoid model. The results from k-space segmented methods (3 to 9 Fourier lines per cardiac cycle for each phase image) were compared with the conventional images of the same short-axis view separately for groups of subjects with normal and reduced ejection fraction. The contrast between blood and myocardium at several sites of the heart and the homogeneity of the blood signal in the ventricle were evaluated for several phases of the heart cycle. RESULTS The segmentation in the acquisition of raw data allows reduction of measuring time to approximately 20% to 40% of the time required for conventional sequences in cine imaging of the heart. In patients with normal or only slightly reduced heart function (ejection fraction > or = 60%) the image quality of k-space segmented sequences was not significantly different from the conventionally recorded images. In contrast, patients with markedly lowered ejection fraction (< 60%) showed degraded results of the k-space segmented sequences compared with the conventional sequence (P < 0.001). The anterolateral border and the right ventricle especially were not sufficiently delineated by the k-space segmented sequences in these patients. CONCLUSION The k-space segmentation for the reduction of examination time is suitable for measuring heart volumes and functional parameters of patients expected to have a nearly normal ejection fraction, whereas for patients with markedly reduced cardiac function further technical improvements of segmented techniques are necessary.

Growth characteristics and imaging properties of the morris hepatoma 3924A in ACI rats: a suitable model for transarterial chemoembolization.

Purpose: For experimental studies investigating modalities and efficacy of transarterial chemoembolization (TACE) in hepatocellular carcinoma (HCC) an animal model resembling the human situation as closely as possible would be appropriate. Specifically, reproducible tumor growth characteristics with the capability for appropriate in vivo imaging to monitor treatment efficacy are required.Methods: Morris hepatoma 3924A was implanted into the liver of 30 ACI rats. Tumor growth was followed by angiography (n=10), ultrasound (US, n=30), native computed tomography (CT. n=16), and native magnetic resonance imaging (MRU n=30) between day 8 and day 36 after implantation. The radiological morphological characteristics were compared with the macroscopic and microscopic histological findings of the explanted tumors.Results: In all 30 animals a solitary liver tumor was found and macroscopically no signs of metastases, ascites, or peritoneal tumor were visible. On histopathological examination tumor sizes ranged between 27 ± 3 mm3 (day 8) and 3468 ± 79 mm3 (day 36). The first signs of tumor necrosis occurred at day 16. US allowed tumor visualization from day 8, MRI from day 8, angiography from day 10, and CT from day 14.Conclusions: The tumor model has the potential to be used for the visualization of tumor growth by MRI and US. The potential for monitoring therapeutic effects of TACE needs to be investigated.

Posttransplant renal artery stenosis--outpatient intraarterial DSA versus color aided duplex Doppler sonography.

A prospective trial was conducted to assess the accuracy of color aided duplex Doppler (CADD) sonography to rule out transplant renal artery stenosis (TRAS) and to determine feasibility and safety of intraarterial digital subtraction angiography (DSA) in hypertensive renal allograft recipients on an outpatient basis. All patients were hypertensive (n = 18, mean age: 42 +/- 11 years) and underwent CADD and an i.a. DSA with 4F catheters. There was a 4 hour rest post DSA. Duplex Doppler measurements of maximum velocity were obtained. Absolute values of > or = 100 cm/s were considered indicative to suspect TRAS. DSA revealed severe TRAS in 4 patients (22%). The stenoses were located near the iliorenal anastomosis (n = 2) and at the bifurcation of the renal artery (n = 2). Duplex Doppler classified twelve (67%) renal artery pedicles normal (maximum velocity: 79 +/- 23 cm/s). TRAS was suspected in 6 patients with a maximum velocity of 159 +/- 48 cm/s (P < 0.01). False positive CADD diagnoses were due to tortuous graft vessels and a postbiopsy arteriovenous fistula. Sensitivity of CADD was 100%, specificity 86%. There were no DSA related complications. No impairment of graft function occurred. CADD allows renal angiography to be reserved to clarify an inconclusive ultrasound study and for definite diagnosis of angiomorphology and lesion classification. Intraarterial DSA of renal grafts in outpatients may be performed without an increased risk of procedure-related complications.

Percutaneous Transhepatic Intraductal Biliary Sonography for Lymph Node Staging at 12.5 MHz in Malignant Bile Duct Obstruction: Work in Progress

PurposeTo assess the value of intraductal ultrasound (US) for lymph node staging in malignant biliary obstruction.MethodsEighteen patients with malignant extrahepatic obstruction were imaged during percutaneous bile duct drainage with a mechanically rotating US transducer at 12.5 MHz. Detectable lymph nodes were classified as malignant when two of three criteria (hypoechoic, rounded, conspicuous margins) were fulfilled. The results were compared with histopathological data in 8 patients and follow-up CT findings in 10 patients.ResultsIn 15 of 18 patients (83%) malignant lymph node involvement was suspected at intraductal US and in 5 of 18 patients (28%) during CT. Histopathological investigation after operation (n=8) and follow-up CT studies (n=10) revealed the presence of malignant nodal involvement in 13 of 18 (72%) patients. The sensitivity, specificity, and accuracy of transhepatic intraductal biliary US in determining merely the presence or absence of malignant lymph nodes without specific topographic assignment were 92%, 40%, and 78%, respectively.ConclusionThese preliminary results suggest that intraductal US may develop into a promising adjunctive modality during percutaneous bile duct drainage in patients with suspected malignant regional lymph node involvement.