Evaluation of patients with liver metastases from colorectal cancer for locally ablative treatment with laser induced thermotherapy. Impact of PET with 18F-fluorodeoxyglucose on therapeutic decisions.

PURPOSE: Before locally ablative treatment of colorectal liver metastases, patients have to be carefully evaluated to decide whether this is the adequate therapy. In this study we determined the value of FDG-PET in comparison to conventional staging procedures. PATIENTS, METHODS: In 68 consecutive patients referred for laser induced thermotherapy (LITT) of liver metastases from colorectal cancer, pretherapeutic staging with conventional imaging (thoracic and abdominal CT, liver MRI, chest X-ray) and FDG-PET was performed. The examinations were analysed separately and blinded. Based on the staging information, therapeutic decisions were made by an interdisciplinary review board according to a standardized algorithm. The results were compared between conventional imaging and FDG-PET, and were validated by clinical follow up data and histopathology, respectively. RESULTS: On FDG-PET 210 lesions were interpreted as tumour manifestations. 48 of these were not seen on conventional imaging (true positive, n = 46). In contrast, 24 lesions were visualized by conventional imaging only (true positive, n = 12). Compared to conventional imaging, discrepant findings on FDG-PET led to treatment modifications in 25 patients (37%); these were correct in 20/25 patients. According to the actual treatment course, the inadequate treatment modifications in the remaining 5 patients were avoided by further diagnostic procedures (i.e. biopsies). CONCLUSION: In the evaluation of patients with known liver metastases from colorectal cancer before LITT, FDG-PET depicts relevant findings subsidiary to conventional imaging and thus is of high value for therapeutic decision making.

Hepatocellular carcinoma in association with hepatic focal nodular hyperplasia.

PURPOSE: To report the association between hepatocellular carcinoma (HCC) and hepatic focal nodular hyperplasia (FNH) and the possible impact on clinical decision-making with regard to resective approaches in patients with FNH. MATERIAL AND METHODS: We retrospectively analyzed the findings in 77 adult patients who underwent liver resections for FNH between October 1989 and September 2001 at our center. HCC within the confines of FNH was found in two patients. We demonstrate the magnetic resonance imaging (MRI) and macroscopic and microscopic findings. RESULTS: Presurgical MRI demonstrated heterogeneous signal characteristics of moderately hyperintense FNH on T2-weighted images and, after i.v. administration of superparamagnetic iron oxide particles, HCC in FNH was barely delineable. Both patients underwent successful right hemihepatectomy to remove the suspicious FNH with diameters of 12 and 14 cm; intralesional HCC diameters were 3 and 5 cm, respectively. Patients could be rapidly dismissed. However, one patient died after recurrence of HCC 1.5 years after surgery, whereas the other patient continues tumor-free 4 years after surgery. Alpha-feto-protein was normal in both patients. CONCLUSION: In FNH with rapid growth tendency and heterogenic MR appearance, surgical removal should be considered to overcome the risk of inadequate therapy in the very rare group of patients with HCC in association with FNH.

Magnetic resonance imaging including magnetic resonance cholangiopancreatography for tumor localization and therapy planning in malignant hilar obstructions.

PURPOSE: To assess image quality and overall accuracy of magnetic resonance imaging (MRI), including two magnetic cholangiopancreatography (MRCP) techniques, for the diagnostics and preoperative work-up of malignant hilar obstructions. MATERIAL AND METHODS: Thirty-one patients with malignant hilar obstructions (hilar cholangiocarcinoma, n=30; hepatocellular carcinoma, n=1) received MRCP by two techniques (single-shot thick-slab and multisection thin-slice MRCP) and unenhanced and contrast material-enhanced MRI. MR assessment included the evaluation of image quality and visualization of bile ducts (5-point scale), and the classification of tumor status. MR results were subsequently correlated with the results from surgery and pathology. RESULTS: The maximum intensity projections of multisection thin-slice MRCP had significantly more artifacts compared to MRCP in the single-shot thick-slab technique, and overall image quality of single-shot thick-slab MRCP was rated significantly superior compared to multisection thin-slice MRCP (4.4 +/- 0.7 and 4.1 +/- 0.9, respectively). Moreover, ductal visualization of different parts of the biliary system was rated superior with single-shot thick-slab MRCP. In contrast, the original data from multisection thin slice MRCP facilitated visualization of periductal lesions and adjacent structures. Overall MR accuracy for the assessment of tumor status, periductal infiltration, and lymph node metastases was 90%, 87%, and 66%, respectively. CONCLUSION: For evaluation of malignant hilar obstructions, MRCP by the single-shot thick-slab technique had superior image quality and fewer artifacts; in contrast, besides sole biliary visualization, multisection MRCP depicted complementary adjacent parenchymal and periductal structures. We therefore recommend MRI, with a combination of both MRCP techniques, for the diagnostic work-up and therapy planning of malignant hilar obstructions.

Computed tomography-guided pulmonary nodule localization before thoracoscopic resection.

PURPOSE: To assess the success rate and complication rate of a CT-guided pulmonary nodule-marker system before thoracoscopic resection. MATERIAL AND METHODS: In 24 patients (15 M, 9 F; age range, 18-71 years) a total of 25 pulmonary nodules (in 1 patient 2 lesions simultaneously) were marked with a special wire under CT-guidance and then thoracoscopically resected. We evaluated lesion size, lesion distance to the pleura, the time of intervention, complications, and thoracoscopic success rate. RESULTS: Mean lesion size was 7 mm (range 4-15 mm) and mean lesional distance to the pleura was 13 mm (range 2-31 mm). The pulmonary nodule-marker system was positioned successfully in all 25 pulmonary nodules within 5-11 min (mean 7.5 min). Minimal pneumothoraces were observed in five patients with no requirements of chest drains. In addition, no bleeding complications or hematothorax were observed. All 25 pulmonary nodules could be resected thoracoscopically. However, in one patient (4%), the guide-wire dislocated during thoracoscopy, but the lesion could be successfully resected during thoracoscopy. CONCLUSION: The CT-guided placement of the pulmonary nodule-marker system used here offers a safe and accurate guide for the localization of small pulmonary nodules during thoracoscopic resection.

Detection of focal liver lesions at biphasic spiral CT: randomized double-blind study of the effect of iodine concentration in contrast materials.

PURPOSE: To evaluate the effect of iodine concentration on the detection of focal liver lesions at biphasic spiral computed tomography (CT). MATERIALS AND METHODS: One hundred two patients (64 men, 38 women) with neoplastic (n = 85) and nonneoplastic focal lesions (n = 17) were prospectively assigned to biphasic injection group A or B and received 180 mL of iopromide containing 370 or 300 mg of iodine per milliliter, respectively, during spiral CT. Comparison included assessment of quantitative and qualitative parameters. RESULTS: Hepatic time-attenuation curves and mean hepatic enhancement in the portal venous phase and aortic time-attenuation curves in both arterial and portal venous phases were statistically superior in group A compared with group B. There was no significant difference in the mean enhancement in all lesions in either group. In contrast, among patients with hepatocellular carcinoma, mean contrast enhancement in lesions in the arterial phase was significantly superior in group A compared with group B. Blinded readers classified hepatic attenuation and lesion visibility as very good and as improved significantly more often in group A than in group B. CONCLUSION: A decrease in iodine concentration significantly affects aortic and hepatic contrast enhancement and may impair the detectability of focal liver lesions during biphasic spiral CT.

Assessment of the vascularization of neuroendocrine tumors by stimulated acoustic emission of SH U 508A ultrasound contrast agent and color or power Doppler sonography.

RATIONALE AND OBJECTIVES: To assess the vascularization of neuroendocrine tumors by stimulated acoustic emission (SAE) of SH U 508A during the blood pool phase in comparison with contrast-enhanced Doppler sonography. METHODS: Thirty-six patients with neuroendocrine tumors received contrast-enhanced Doppler sonography and 21, an additional SAE. To classify tumor perfusion on Doppler sonography, a 4-step rating score was introduced: (1) no vessels (hypoperfusion); (2) one feeding or central vessel (hypoperfusion); (3) some vessels (hyperperfusion); and (4) disseminated vessels (hyperperfusion). In 36 patients, 1 pancreatic primary tumor, 33 liver metastases, 1 splenic metastasis, and 1 lymph node metastasis were examined. Results were correlated with biphasic spiral CT (n = 35) and angiography (n = 2). RESULTS: Arterial-phase CT and digital subtraction angiography revealed 18 hyper- and 18 hypoperfused lesions. Contrast-enhanced Doppler correctly classified 15 of 18 patients (83%) with hyperperfused lesions as well as 16 of 18 (89%) hypoperfused tumors by applying the rating score. SAE correctly identified 4 of 9 hyperperfused lesions (44%), 2 were isoperfused compared with normal liver tissue (22%), and 3 were hypoperfused (33%). Of 12 hypoperfused lesions, 11 were classified correctly (92%), and 1 showed isoperfusion. Hence, the positive and negative predictive values for SAE were 80% and 69%, respectively. For contrast-enhanced Doppler sonography, positive and negative predictive values were 88% and 84%, respectively. CONCLUSIONS: Blood pool SAE failed to determine subtle tumor perfusion correctly. The rating score for contrast-enhanced Doppler sonography characterized tumor perfusion with high accuracy. The use of a contrast agent significantly improved perfusion characterization.

Shortcomings of low-cost imaging systems for viewing computed radiographs.

OBJECTIVE: To assess potential advantages of a new PC-based viewing tool featuring image post-processing for viewing computed radiographs on low-cost hardware (PC) with a common display card and color monitor, and to evaluate the effect of using color versus monochrome monitors. MATERIALS AND METHODS: Computed radiographs of a statistical phantom were viewed on a PC, with and without post-processing (spatial frequency and contrast processing), employing a monochrome or a color monitor. Findings were compared with the viewing on a radiological Workstation and evaluated with ROC analysis. RESULTS: Image post-processing improved the perception of low-contrast details significantly irrespective of the monitor used. No significant difference in perception was observed between monochrome and color monitors. The review at the radiological Workstation was superior to the review done using the PC with image processing. CONCLUSION: Lower quality hardware (graphic card and monitor) used in low cost PCs negatively affects perception of low-contrast details in computed radiographs. In this situation, it is highly recommended to use spatial frequency and contrast processing. No significant quality gain has been observed for the high-end monochrome monitor compared to the color display. However, the color monitor was affected stronger by high ambient illumination.

Biphasic spiral computed tomography versus digital subtraction angiography for evaluation of arterial thrombosis after orthotopic liver transplantation.

RATIONALE AND OBJECTIVES: The authors characterize the spiral computed tomographic (CT) findings in patients with hepatic arterial thrombosis after orthotopic liver transplantation (OLT). METHODS: In nine with and 15 patients without hepatic artery thrombosis (HAT) after OLT, unenhanced and contrast-enhanced biphasic spiral CT was performed during arterial and venous phases, and evaluated by consensus of two blinded readers. Evaluation included signs of parenchymal and vascular changes in the liver. Findings subsequently were correlated with those of digital subtraction angiography (DSA). RESULTS: Among all patients, eight had complete occlusion of the proximal hepatic artery and one patient had partial thrombosis, as revealed by conventional DSA. Characteristic CT findings of HAT included irregularly shaped confluent hypoattenuating liver areas (n = 8), seen both before and after administration of contrast material. Necrotic lesions and changes consistent with ischemic type of biliary lesion were documented in six patients. Biphasic CT allowed detection of HAT in eight patients. Because of inadequate contrast enhancement during the arterial phase, thrombosed intrahepatic arteries were not adequately diagnosed in one patient. Overall CT sensitivity to detect HAT was 89%, specificity was 100%. CONCLUSIONS: Characteristic biphasic spiral CT findings in hepatic artery thrombosis contribute to early detection of arterial thrombosis after OLT and are helpful for planning more invasive diagnostic approaches.

[Comparative findings of digital thoracic images and digital images of statistical phantoms as film copy, a radiological work station and a PC]. / Vergleichende Befundung von digitalen Thoraxbildern und digitalen Aufnahmen eines statistischen Phantoms als Filmkopie, an einer radiologischen Workstation und an einem PC.

INTRODUCTION: An ROC analysis was carried out in order to determine the reliability of digital luminescence radiography review at a PC and this was compared with a radiological work station and with X-ray film on a viewing box. MATERIAL AND METHOD: 54 chest images obtained by digital luminescence radiography were selected, 31 of these contained small pulmonary nodules. In order to evaluate critical detail, five images of a phantom showing round foci were used. Five radiologists examined these, using a Siemens Magic View work station, a PC with proprietary software (ViewMed) and X-ray films on a viewing box. Image processing of the work station used the standard clinical application. ViewMed performs linear scaling of grey levels to 8 Bit. The results were examined statistically by means of a t-test. RESULTS: As far as the chest images were concerned there was no significant difference in the diagnostic value of these methods. There was, however, a highly significant loss of diagnostic information with respect to the round focus phantom when using the PC compared with the other methods. CONCLUSION: In the configuration in which it was used, the PC should not be relied on as a primary means of examination since critical details cannot always be seen. In routine use these play a subordinate role and there was no significant diagnostic loss where the chest images were concerned. We expect that by improvements in the frequency and contrast processing the PC accuracy will be considerably increased.

Cytogenetic studies in renal cell carcinoma patients receiving low-dose recombinant interleukin-2-based immunotherapy.

A variety of cytogenetic aberrations have been reported in sporadic and familial renal cell carcinoma. Rearrangements of the short arm of chromosome 3 (3p), trisomy 17, and nuclear hyperdiploidy have been reported to be common clonal chromosome changes. We analyzed a total of ten tumor-derived cell lines from patients who underwent nephrectomy for renal cell carcinoma employing conventional cytogenetics. All patients received an immunomodulatory therapy based on recombinant interleukin-2 (rIL-2). Tumor stage and grade, histo- and cytopathology, and patients' response to immunotherapy were assessed and correlated statistically to rearrangement of 3p, trisomy 17, and nuclear hyperdiploidy. Trisomy 17 as clonal aberration could be revealed only in papillary renal cell carcinoma, whereas tumors with compact or tubulopapillary growth pattern lacked this abnormality (p < 0.002). One of 3 patients with diploid or near-diploid karyotype (< or = 49 chromosomes) achieved a partial remission while two presented with stable disease after immunotherapy. In contrast, all 6 patients with tumor progression upon rIL-2-based immunotherapy revealed hyperdiploid (> 49 chromosomes) karyotypes. The correlation between hyperdiploidy and tumor progression was found to be statistically significant (p < 0.029). Interestingly, the only patient achieving an objective tumor remission after immunotherapy presented with a normal diploid karyotype. Our findings suggest tumor hyperdiploidy as an adverse prognostic factor in renal cell carcinoma patients receiving rIL-2-based immunotherapy.

Lymphocyte-conditioned medium in combination with interleukin-2 effectively induces antitumour autoimmunity by adoptive transfer of short activated killer (SHAK) cells.

In this study, effective antitumour immunity was transferred by autologous short activated killer (SHAK) cells induced over four hours with lymphocyte conditioned medium (LCM) and recombinant interleukin-2 (rIL-2). Among eight patients with progressive metastatic renal cell carcinoma refractory to standard therapy, there were six objective tumour responses to SHAKs. Progression-free survival ranged from 0 to 8+ months, and overall survival ranged from 2 to 14+ months, with a median of 9+ months. Systemic toxicity of SHAKs was limited to flulike symptoms. Patient SHAKs provided a tumour-specific immunity, both cellular and humoral (expression and secretion of secondary cytokines, including IL-2, GM-CSF, INF-gamma and TNF-alpha), far superior to rIL-2 activated killer cells.

In vivo tumor necrosis factor-alpha as indicator of biologic and clinical response to low-dose SC recombinant interleukin 2.

The effect of low-dose human recombinant interleukin-2 (rIL-2) on the induction of secondary tumor necrosis factor-alpha (TNF-alpha) in vivo was studied in 16 patients with metastatic renal cell carcinoma. In all patients s.c. rIL-2 resulted in a significant increase in TNF-alpha serum levels within 4 to 8 hours, as determined by enzyme-linked immunosorbent assay (ELISA). TNF-alpha serum concentrations remained elevated up to 24 hours following single s.c. administration of rIL-2. Total secondary TNF-alpha release, as assessed by the area under the curve (AUC), appeared to be independent of dose distribution of rIL-2 (10 million IU rIL-2 q12 hours versus 20 million IU rIL-2 q24 hours). rIL-2 induced TNF-alpha release was significantly higher in patients who had received prior rIL-2 immunotherapy, while steroids resulted in a significant suppression of TNF-alpha release. Secondary TNF-alpha release was statistically associated with progression-free survival of renal cell carcinoma patients and may be a prognostic factor in patients receiving rIL-2.

Treatment of metastatic colorectal cancer patients with 5-fluorouracil in combination with recombinant subcutaneous human interleukin-2 and alpha-interferon.

We treated 14 patients with progressive metastatic colorectal cancer, using a combination of subcutaneous recombinant human interleukin-2 (4.8 x 10(6) IU/m2 three times daily on days 1 and 22, and twice daily on days 2 and 23, followed by 2.4 x 10(6) IU/m2 twice daily on days 3-5, 8-12, 24-26, and on 5 consecutive days per week, starting day 29), recombinant human interferon-alpha 2a (5.0 x 10(6) U/m2 thrice weekly), and 5-fluorouracil (750 mg/m2 i.v. bolus on days 15-19, and at weekly intervals thereafter, with a 1-week off-therapy interval every 4 weeks). Therapy was continued until disease progression occurred. Four (29%) and 8 (57%) evaluable patients achieved partial remission and stable disease, respectively; median response duration was 5.9 months. Toxicity of this regimen was moderate; the most common side effects were thrombocytopenia, leukopenia, nausea/vomiting, anorexia, malaise and fevers in all patients, along with diarrhea (63%) and mucositis (54%). Less than 10% of patients developed WHO grade IV toxicity; no toxic deaths occurred. Efficacy of this combination was not substantially different from alternative 5-fluorouracil-based regimens.

In vivo time and dose dependency of interleukin-6 secretion in response to low-dose subcutaneous recombinant interleukin-2.

Serum concentrations of Interleukin-6 (IL-6) were determined in renal cell carcinoma patients treated with low-dose subcutaneous human recombinant interleukin-2 (rIL-2). In all patients, administration of rIL-2 resulted in a significant increase in IL-6 serum levels to peak values within 4 to 6 hours as measured by enzyme-linked immunosorbent assays (ELISA). Repetitive administration of rIL-2 induced significantly lower IL-6 serum peaks when compared to the initial administration of rIL-2. Cumulative IL-6 release, as expressed by the area under the concentration curve (AUC), appeared to be independent of rIL-2 dose distribution (10 million IU rIL-2/m2 versus 20 million IU rIL-2/m2), and IL-6 serum peaks showed no direct dose dependency. Prior rIL-2 immunotherapy had no measurable effect on rIL-2 induced IL-6 release, while steroids resulted in a significant suppression of secondary IL-6 did not correlate with response to rIL-2 therapy or survival of rIL-2 treated renal cell carcinoma patients.

Interleukin-2 in combination with interferon-alpha and 5-fluorouracil for metastatic renal cell cancer.

Recent clinical trials for the biological therapy of solid tumours have used recombinant human cytokines in combination with conventional chemotherapy. In patients with progressive metastatic renal cell carcinoma, we established a three-drug combination comprising interferon-alpha (IFN-alpha), interleukin-2 (IL-2) and 5-fluorouracil (5-FU), using a regimen which allows outpatient therapy. Treatment consisted of 8 weeks each of IFN-alpha [6-9 MU/m2 once to three times weekly subcutaneously (sc)] combined sequentially with IL-2 (5-20 MU/m2 thrice weekly sc for 4 weeks) and 5-FU [750 mg/m2 intravenously (i.v.) weekly for 4 weeks]. Among the first 35 patients treated, there were 4 complete (11.4%) and 13 partial responders (37.1%), with an overall objective response rate of 48.6% (95% confidence interval 32-66%). Regressions occurred in local relapse, in lung, lymph node, bone, pleural, renal and thyroid metastases. Median response duration was calculated at 7+ months. An additional 13 patients (37.1%) were stable throughout therapy and thereafter (median of 6+ months). Response rate of this three-drug combination regimen compared favourably with single agent IFN-alpha (objective response rate approximately 16%) and against the sc IFN-alpha/IL-2 combination (objective response rate approximately 28%). Systemic toxicity was mild to moderate with no severe 5-FU-related mucositis and no dose-limiting adverse effects of sc IL-2. While the exact mechanisms of the potentially additive or synergistic effects of 5-FU and IFN-alpha/IL-2 remain to be established in more detail, it appears that the sequential use of IFN-alpha/IL-2 and IFN-alpha/5-FU in metastatic renal carcinoma further enhances the therapeutic index of IFN-alpha/IL-2-based biological therapy. Based on the present data, combined biochemotherapy may be a promising new approach to the therapy of advanced renal cancer.

Immunogenicity of recombinant human interleukin-2: biological features and clinical relevance.

The immunogenicity of recombinant interleukin-2 (rIL-2, EuroCetus, Amsterdam, Netherlands) was studied in seventy-six patients receiving different subcutaneous immunotherapy regimens. Patients presented with progressive metastatic renal cell carcinoma, malignant melanoma, colorectal cancer, B-cell lymphoma, and Hodgkin's disease. An enzyme immunoassay (EIA) was employed to screen patients for development of non-neutralizing antibodies against rIL-2, antibody specificity was confirmed by a standard Western blot. Neutralizing serum activity against rIL-2 was detected using a standard CTLL mouse proliferation assay. Additionally, serum levels of soluble interleukin-2 receptors and lymphocyte subsets expressing the CD56 natural killer (NK) associated antigen were measured. In a proportion of approximately 35% to 90% of the patients treated, non-neutralizing antibodies against rIL-2 could be detected after all treatment courses were evaluated. Antibodies were of the IgG, IgM, IgA and IgD subtypes. None of the 76 patients exhibited serum neutralizing activity after one treatment course. Five patients exhibited neutralizing anti-rIL-2 serum activity after two or more treatment courses of systemic rIL-2. In three of these patients, antibodies neutralized both recombinant and natural IL-2. Patients developing neutralizing anti-rIL-2 antibodies, exhibited significantly lower serum sIL-2 receptor levels upon the emergence of serum neutralizing activity than patients without antibody. Additionally, NK cell associated CD56 positivity was significantly lower in patients who exhibited neutralizing anti-rIL-2 serum activity than in patients who did not. A significant decrease in levels of soluble IL-2 receptors and CD56 NK cell positivity was observed, when comparing values prior to and after onset of serum neutralizing activity against rIL-2. However, while emergence of neutralizing antibodies to rIL-2 diminished rIL-2 induced biological activation, it did not coincide with abrogation of treatment response.

Biological monitoring of low-dose interleukin 2 in humans: soluble interleukin 2 receptors, cytokines, and cell surface phenotypes.

Different immunotherapy regimens using s.c. recombinant interleukin-2 (rIL-2) were studied in 76 patients with progressive metastatic renal carcinoma, malignant melanoma, colorectal cancer, B-cell lymphoma, or Hodgkin's disease. To assess the immunomodulatory capacity of rIL-2, we measured serum levels of soluble interleukin-2 (sIL-2) receptors, gamma-interferon, tumor necrosis factor-alpha, and various lymphocyte subsets expressing the CD25 Tac IL-2 receptor and the CD56 natural killer (NK) associated antigen. Additionally, we measured serum antibodies specific to rIL-2 in order to evaluate immunogenicity of rIL-2. In all patients, a significant increase in sIL-2 receptor levels could be observed when comparing values on day 0 and after one treatment course. Patients developing a neutralizing anti-rIL-2 antibody exhibited significantly lower serum sIL-2 receptor levels than patients without antibody. Soluble IL-2 receptors correlated with the percentage of CD25 IL-2 receptor-positive peripheral blood lymphocytes. Both soluble and cell surface IL-2 receptors exhibited a significant increase during rIL-2 therapy but did not correlate with the percentage of CD56-positive peripheral blood lymphocytes. Measurement of treatment-induced secondary cytokines showed significant increases in gamma-interferon serum levels in a proportion of patients tested, although with considerable interindividual variability. No significant increase in mean tumor necrosis factor-alpha levels was observed during rIL-2 treatment in vivo. The percentage of CD56-positive NK cells correlated with the clinical outcome of rIL-2 therapy. Thus, partial or complete responders had an increase from a mean of 20% NK cells prior to therapy up to a mean of 40% after the first treatment course. In contrast, patients with progressive disease had a mean of 22 and 24% NK cells before and after treatment, respectively.