Klaus-Jochen Klose

Placebo-Controlled, Double-Blind, Prospective, Randomized Study on the Effect of Octreotide LAR in the Control of Tumor Growth in Patients With Metastatic Neuroendocrine Midgut Tumors: A Report From the PROMID Study Group

4508 Background: Octreotide is currently used for the control of symptoms in patients with gastroenteropancreatic neuroendocrine tumors (NETs). However, the ability of long-acting somatostatin analogues to control the growth of well-differentiated metastatic NETs is a matter of debate. The analysis of the first randomized, double-blind, placebo-controlled, multicenter, phase IIIb study of octreotide LAR in patients with metastatic NETs of the midgut is presented. METHODS Treatment-naïve patients with histologically confirmed locally inoperable or metastasized well-differentiated NETs and a Karnofsky index >60 were randomized to receive either octreotide LAR 30 mg/month (mo) or placebo for 18 mos, or until tumor progression or death. The primary endpoint was median time to tumor progression. Secondary endpoints included objective tumor response rate (WHO criteria), measured every 3 mos, as well as symptom control and overall survival. This was a planned interim analysis using the Lan-DeMets error spending approach. RESULTS Eighty-five patients (n=43 octreotide LAR; n=42 placebo) have been enrolled to date and data from 67 patients with tumor progressions and 16 deaths (n=7 octreotide LAR; n=9 placebo) are included here. Median time to tumor progression in the octreotide LAR and placebo groups were 14.3 mos and 6 mos, respectively (HR: 0.34; 95% CI: 0.20-0.59; P=0.000072). After 6 mos of treatment, stable disease was seen in 67% and 37.2% of patients treated with octreotide LAR and placebo, respectively. Due to the low number of observed deaths, median survival time could not be estimated. CONCLUSIONS Octreotide LAR significantly lengthens median time to tumor progression compared with placebo in patients with metastatic NETs of the midgut. Patients treated with octreotide LAR had a 66% risk reduction of tumor progression compared with patients receiving placebo. Octreotide LAR demonstrates substantial tumor control and shows a more favorable antiproliferative response than placebo as two-thirds of patients treated with octreotide LAR achieved stable disease at 6 mos. [Table: see text].PURPOSE Somatostatin analogs are indicated for symptom control in patients with gastroenteropancreatic neuroendocrine tumors (NETs). The ability of somatostatin analogs to control the growth of well-differentiated metastatic NETs is a matter of debate. We performed a placebo-controlled, double-blind, phase IIIB study in patients with well-differentiated metastatic midgut NETs. The hypothesis was that octreotide LAR prolongs time to tumor progression and survival. PATIENTS AND METHODS Treatment-naive patients were randomly assigned to either placebo or octreotide LAR 30 mg intramuscularly in monthly intervals until tumor progression or death. The primary efficacy end point was time to tumor progression. Secondary end points were survival time and tumor response. This report is based on 67 tumor progressions and 16 observed deaths in 85 patients at the time of the planned interim analysis. RESULTS Median time to tumor progression in the octreotide LAR and placebo groups was 14.3 and 6 months, respectively (hazard ratio [HR] = 0.34; 95% CI, 0.20 to 0.59; P = .000072). After 6 months of treatment, stable disease was observed in 66.7% of patients in the octreotide LAR group and 37.2% of patients in the placebo group. Functionally active and inactive tumors responded similarly. The most favorable effect was observed in patients with low hepatic tumor load and resected primary tumor. Seven and nine deaths were observed in the octreotide LAR and placebo groups, respectively. The HR for overall survival was 0.81 (95% CI, 0.30 to 2.18). CONCLUSION Octreotide LAR significantly lengthens time to tumor progression compared with placebo in patients with functionally active and inactive metastatic midgut NETs. Because of the low number of observed deaths, survival analysis was not confirmatory.

Transarterial Chemoembolization of Advanced Liver Metastases of Neuroendocrine Tumors – A Retrospective Single-Center Analysis

Background: In neuroendocrine tumors, metastases are a negative prognostic factor for survival and quality of life. Transcatheter arterial chemoembolization (TACE) is thought to be an effective symptomatic and antiproliferative treatment in patients with otherwise progressive disease. Methods: 62 chemoembolization procedures in 26 patients with progressive neuroendocrine tumors were reviewed. The underlying disease was carcinoid syndrome in 10, non-functional midgut tumor in 2, non-functional pancreatic tumor in 7, malignant insulinoma in 2 patients, non-functional tumor of the stomach in 1 and of unknown origin in 4 patients. Tumor burden of the liver was <25% in 3, 25–50% in 11, 50–75% in 6 and >75% in 6 patients. Results: TACE was technically successful in 57 cases. Four patients developed minor and 5 major complications. The 30-day mortality rate was 7.7%. According to WHO criteria, 14 patients had no change in tumor burden, 2 had regression and 5 progress after chemoembolization. Patients with a tumor burden >75% of the liver did not benefit from TACE due to the development of major complications, whereas patients with low (<50%) tumor burden and high (>50%) lipiodol uptake showed a trend towards longer survival. Five-year survival time after diagnosis was 48%. Patients treated with octreotide and/or α-interferon had no benefit from chemoembolization with regard to their carcinoid syndrome. Conclusions: In this retrospective study, patients with low (<50%) tumor burden and high (>50%) lipiodol uptake responded better to TACE than end-stage patients.

Selective Internal Radiotherapy with Yttrium-90 Microspheres for Hepatic Metastatic Neuroendocrine Tumors: A Prospective Single Center Study

Background: To assess prospectively the safety and efficacy of Yttrium-90 microspheres in patients with unresectable liver metastases from neuroendocrine tumors. Materials and Methods: Microspheres were administered via a temporarily placed hepatic catheter. Patients were monitored prospectively. All patients were followed with laboratory and imaging studies at regular intervals to determine response rates. Toxicity and quality of life scores were measured. Results: Nine patients (7 female) with a mean age of 58.8 years were enrolled in this prospective trial. The mean tumor load was 58.8%. The estimated percentage shunting to the lungs on MAA scans was 5.04 ± 2.4%. Visceral artery embolization of extrahepatic arteries before treatment was performed in 6 patients. The median dose of microspheres was 2.1 ± 0.4 GBq. A total of 12 therapy sessions was performed. The mean follow-up was 21.7 months. Technical success was 100%. No major complications occurred. Survival rates were 100, 57 and 57% for 1, 2 and 3 years, respectively. Three months after SIRT therapy partial response (PR) was seen in 6 patients (66%). Calculated reduction of liver metastasis volume was 49%. In 3 patients (33%) stable disease was seen with a calculated tumor reduction of 13%. The estimated time to progression was 11.1 months. Conclusion: Radioembolization with 90Y microspheres is safe and produces high response rates even with extensive tumor replacement for up to 1 year. Acute and late toxicity was very low. Further investigations compared with other local ablative techniques is warranted.

A new balloon-expandable tantalum stent (Strecker-Stent) for the biliary system : preliminary experience

Placement of a balloon-expandable metallic stent (Strecker-Stent) for biliary drainage has been attempted in 30 patients. The stent was successfully implanted in 22 patients; in the remaining 8 patients, dilatation of the biliary stricture prior to stent placement was inadequate and delivery of the Strecker-Stent was, therefore, not possible. Insufficient balloon dilatation was related to the rigid nature of the stricture and to pain experienced during dilatation. During 2–9 months follow-up, 3 of 21 patients (14%) presented with reocclusion of the stented bile ducts. In all other patients, biliary drain-age remains adequate. No major complications related to stent placement were observed.

The use of gadolinium chelates for X-ray digital subtraction angiography.

Wagner H-J, Kalinowski M, Klose K-J, et al. The use of gadolinium chelates for x-ray digital subtraction angiography. Invest Radiol 2001:36:257–265. rationale and objectives. To evaluate the feasibility and safety of using gadolinium chelates for x-ray digital subtraction angiography (DSA) in patients with contraindications to iodinated contrast material. methods.We performed 30 DSAs in 22 patients (5 females, 17 males; mean age 64.9 years) with contraindications to iodinated contrast media (renal insufficiency:n = 28; hyperthyroidism:n = 1; contrast allergy:n = 2). Gadolinium chelates were administered as 0.5 mol/L solutions (mean volume of gadolinium chelates per patient was 34 ± 19 mL). Gadolinium chelates were the sole contrast agent in 17 examinations, were used in conjunction with carbon dioxide (CO2) in 8 studies, (mean 212 ± 226 mL), and were combined with the restricted use of nonionic iodinated contrast (mean 12.8 ± 4.7 mL) in 6 examinations. We carried out 15 diagnostic angiographies and 15 percutaneous transluminal angioplasties. results.Use of gadolinium chelates allowed us to obtain diagnostic angiographic images in all cases. However, the quality of angiograms was inferior compared with that obtained with iodinated contrast agents and superior compared with CO2 as the contrast material. Adverse events were not noted. Mean serum creatinine was 2.6 ± 1.5 mg/dL before and 2.3 ± 1.0 mg/dL after DSA. No patient developed contrast-induced nephropathy. conclusions.Gadolinium chelates produce an x-ray DSA intermediate in image quality between iodinated contrast and CO2. Digital subtraction angiography with intra-arterial gadolinium chelate administration may offer an alternative to iodinated contrast material in patients with contraindications to iodine.

Correlation of flow velocity measurements by magnetic resonance phase contrast imaging and intravascular Doppler ultrasound.

RATIONALE AND OBJECTIVES The authors compare the magnetic resonance (MR) phase contrast flow velocity measurements in varying concentric stenoses with invasive measurements obtained with a Doppler guidewire. METHODS Flow velocity measurements were obtained using a calibrated 0.018 inch 12 MHz Doppler guidewire and a 1.0 T MR imaging system in a pulsatile hydraulic model with variable arterial stenoses. Velocity measurements were performed proximal, intrastenotic, and distal to the stenoses. The cross-sectional area of stenosis was calculated from the data of both methods. For MR imaging measurements, fast low-angle shot two-dimensional phase contrast sequences with different velocity encodings were used. RESULTS Phase contrast flow measurements correlated well (r = 0.95, Pearson) with Doppler guidewire-based flow velocity data. Generally, flow velocities obtained with MR imaging were lower when compared with the Doppler-based data (P < or = 0.001, Wilcoxon matched pairs test). However, the ratios and the calculated cross-sectional area of stenoses showed a high correlation (r = 0.96) with the predefined area of stenoses. CONCLUSIONS The assessment of flow alterations in vitro due to variable stenoses using MR phase contrast flow measurements is very well correlated with the Doppler guidewire. Consequently, these results required in vivo measurements of atherosclerotic lesions to evaluate the clinical impact.

“Activity based costing” in der Radiologie

ZusammenfassungHintergrund. Die Ökonomisierung der Medizin in Deutschland, die in der beabsichtigten Einführung der kostenhomogenen Vergütungsklassen nach den “diagnosis related groups – DRGs” ihren vorläufigen Höhepunkt finden soll, erfordert eine Neuorientierung im Einsatz und in der Beurteilung der Wirtschaftlichkeit radiologischer Verfahren. Methode. Traditionelle Kostenrechnungen bzw. Verfahren zur internen Budgetierung werden der Prozesskostenbetrachtung (“activity based costing”– ABC) gegenübergestellt, deren auf radiologische Belange zugeschnittene Methodik Schritt für Schritt entwickelt wird. Ergebnisse. Die Betrachtung radiologischer Arbeitsprozesse auf der Basis des ABC gestattet anhand der bisher publizierten Ergebnisse eine bessere Einschätzung von Steuerungsimpulsen, die zu einer Effizienzsteigerung in radiologischen Prozessen führen können. Schlussfolgerungen. Die Einführung einer prozessorientierten Kostenanalyse ist für vielfältige Belange einer Radiologieabteilung möglich. Sie stellt einen zentralen Baustein in der Entwicklung eines abteilungsinternen und damit dezentralen Controlling dar und ist damit als strategische Unternehmensaufgabe anzusehen, da hiermit eine handlungsrelevante Beurteilung der Geschäftsprozesse möglich ist.Die hierfür nötigen Arbeiten im Sinne der Prozessanalyse lassen sich synergistisch für andere Zwecke (Zertifizierung, Digitalisierung) nutzen.AbstractBackground: The introduction of diagnosis related groups for reimbursement of hospital services in Germany (g-drg) demands for a reconsideration of utilization of radiological products and costs related to them. Methods: Traditional cost accounting as approach to internal, department related budgets are compared with the accounting method of activity based costing (ABC). The steps, which are necessary to implement ABC in radiology are developed. Conclusions: The introduction of a process-oriented cost analysis is feasible for radiology departments. ABC plays a central role in the set-up of decentralized controlling functions within this institutions. The implementation seems to be a strategic challenge for department managers to get more appropriate data for adequate enterprise decisions. The necessary steps of process analysis can be used for other purposes (Certification, digital migration) as well.

Epiphysenfugenverletzungen der distalen Tibia Sinnvolle Mehrinformation durch die MRT

ZusammenfassungDie konventionelle Röntgendiagnostik unterschätzt häufig das Ausmaß der kindlichen Extremitätenfrakturen mit Epiphysenbeteiligung (Typ Salter-Harris). Insbesondere werden die Kompressionsfrakturen der Wachstumsfuge (Salter-Harris V) primär häufig nicht erkannt. Prospektiv wurden 10 Kinder im Alter von 9–17 Jahren (Durchschnittsalter=14 J.) mit Verdacht auf eine epiphysäre Fraktur der distalen Tibia magnetresonanztomographisch (1.0-Tesla Magnetom Expert), untersucht. Die MRT-Ergebnisse wurden auf der Basis der Klassifikation nach Salter-Harris-Rang-Odgen mit den konventionellen Röntgenbildern verglichen. In einem Fall, bei einem 15jährigen Patienten, gelang durch die MRT der Ausschluß einer epiphysären Verletzung. In 7 Fällen führte der MRT-Einsatz zu einer Änderung der Klassifikation nach Salter-Harris. Hieraus resultierte bei 4 Patienten ein Therapiewechsel. Da Frakturen, die sie begleitenden Knorpelläsionen und ligamentäre Verletzungen multiplanar dargestellt werden können, weist die MRT deutliche Vorteile gegenüber jeder anderen diagnostischen Methode (z.B. konventionelle Röntgendiagnostik, CT) auf. Im Hinblick auf die Strahlenexposition ist sie besonders bei Kindern eindeutig zu bevorzugen.SummaryPlain film radiography often underestimates the extent of injury in children with epiphyseal fracture. Especially Salter-Harris V fractures (crush fracture of the epiphyseal plate) are often primarily not detected. MRI of the ankle was performed in 10 children aged 9–17 (mean 14) years with suspected epiphyseal injury using 1.0-T Magnetom Expert. The fractures were classified according to the Salter-Harris-Rang-Odgen classification and compared with the results of plain radiography. In one case MRI could exclude epiphyseal injury; in four cases the MRI findings changed the therapeutic management. The visualisation of the fracture in three orthogonal planes and the possibility of detection of cartilage and ligamentous injury in MR imaging makes this method superior to conventional radiography and CT. With respect to radiation exposure MRI instead of CT should be used for the dignosis of epiphyseal injuries in children.

Kinetic evaluation of an I.V. bolus of MR contrast media

Currently, it is assumed that the pharmacokinetic properties of the first minutes of an I.V. MR contrast media bolus are similar to those of an i.v. iodinated contrast media bolus used in CT. Correct timing of an MRA examination is crucial for obtaining sufficient arterial contrast. This study sought to evaluate the temporal change of arterial signal intensity within 150 s after i.v. bolus injection of Gd-DTPA. Thirty consecutive patients (14 women/16 men; mean age: 51 +/- 11 years) were prospectively examined with a 1.0 Tesla clinical scanner. A single axial slice was acquired in 1.25 sec with manufacturer provided gradient echo sequence through the aorta at the level of the renal arteries. Investigation was started simultaneously to the application of contrast media (0.1 mmol/kg bodyweight Gd-DTPA at three different rates 2 mL/sec, 3 mL/sec and 4 mL/sec) and repeated for 2.5 min. An additional echo Doppler examination excluded patients with any cardiac disorders. Maximum signal (1300% increase compared to the basic value) in the aorta was achieved 20 +/- 6 sec after start of bolus injection. Then a plateau phase was maintained for the remaining investigation time (2.5 min). No significant difference was shown for different injection rates. After a bolus injection of Gd-DTPA the arterial contrast remains on a high level for at least 2 min. However, correct timing of the bolus arrival is still crucial to discriminate arteries and veins. An injection rate between 2 mL/sec and 4 mL/sec has no influence on early contrast media dynamics.

Propofol versus midazolam for sedation during percutaneous transluminal angioplasty.

PURPOSE To prospectively and randomly compare use of propofol versus midazolam for sedation during percutaneous transluminal angioplasty (PTA). MATERIALS AND METHODS Forty patients (27 men, 13 women; mean age 64.4 years +/- 12.2) who underwent PTA of the arteries below the diaphragm were prospectively randomized for sedation with propofol or midazolam. Both drugs were administered after an initial bolus injection by means of continuous infusion to achieve conscious sedation at levels II-III according to the Ramsay classification. Patients and interventionalists were blinded to the applied sedative. Both groups were similar with regard to American Society of Anesthesiology status, heart rate, blood pressure, arterial oxygen pressure (pO2), arterial carbon dioxide pressure (pCO2), arterial oxygen saturation (SpO2), and visual analogue scores for general condition, anxiety, and pain. During PTA, heart rate, blood pressure, and pulse oximetry (tpO2) were monitored continually. Every 30 minutes, an arterial blood gas analysis was performed. Visual analogue scores were obtained before, during, and after intervention. RESULTS Decreases in SpO2, pO2, and tpO2 were significantly greater after sedation with midazolam (P < .05; t test). The increase in pCO2 was significantly greater after midazolam (P < .05; t test). No significant difference between the drugs was found with regard to any of the other parameters. Both drugs resulted in sufficient sedation and anxiolysis (P < .01 for both drugs for visual analogue score for anxiety before and during PTA; matched pairs test). Satisfaction of the interventionalist was significantly greater for propofol (P < .05; t test). CONCLUSION Propofol causes less respiratory depression than midazolam for equivalent sedation and anxiolysis in patients undergoing PTA.