[Treatment of patients with radioiodine refractory, differentiated thyroid carcinoma. A Consensus Statement]. / Therapie des Patienten mit Radioiod-refraktärem, differenziertem Schilddrüsenkarzinom. Ein Konsensusstatement.

There is no clear standard therapy for patients with radioactive iodine (131I)-refractory locally advanced or metastatic differentiated thyroid cancer. The therapeutic options for this indication have expanded with the recently approved multiple kinase inhibitor sorafenib. Recommendations for the definition and the management of iodine refractory patients were worked up by an interdisciplinary expert panel, consisting of endocrine surgeons, medical oncologists and nuclear medicine specialists.

Dose escalation to rash for erlotinib plus gemcitabine for metastatic pancreatic cancer: the phase II RACHEL study.

BACKGROUND: This phase II, open-label, randomised study evaluated whether patients with metastatic pancreatic cancer receiving erlotinib/gemcitabine derived survival benefits from increasing the erlotinib dose. METHODS: After a 4-week run-in period (gemcitabine 1000 mg m(-2) once weekly plus erlotinib 100 mg per day), patients with metastatic pancreatic cancer who developed grade 0/1 rash were randomised to receive gemcitabine plus erlotinib dose escalation (150 mg, increasing by 50 mg every 2 weeks (maximum 250 mg); n=71) or gemcitabine plus standard-dose erlotinib (100 mg per day; n=75). The primary end point was to determine whether overall survival (OS) was improved by increasing the erlotinib dose. Secondary end points included progression-free survival (PFS), incidence of grade ⩾2 rash, and safety. RESULTS: Erlotinib dose escalation induced grade ⩾2 rash in 29 out of 71 (41.4%) patients compared with 7 out of 75 (9.3%) patients on standard dose. Efficacy was not significantly different in the dose-escalation arm compared with the standard-dose arm (OS: median 7.0 vs 8.4 months, respectively, hazard ratio (HR), 1.26, 95% confidence interval (CI): 0.88-1.80; P=0.2026; PFS: median 3.5 vs 4.5 months, respectively, HR, 1.09, 95% CI: 0.77-1.54; P=0.6298). Incidence of adverse events was comparable between randomised arms. CONCLUSION: The erlotinib dose-escalation strategy induced rash in some patients; there was no evidence that the higher dose translated into increased benefit.

Primary epiploic appendagitis and fructose malabsorption.

Primary epiploic appendagitis (PEA) is a rare cause of abdominal acute or subacute complaints. Diagnosis of PEA is made when computed tomography (CT) reveals a characteristic lesion. We report on contrast-enhanced CT images of a patient with PEA and regression of inflammation and the reduction in size of the inflamed appendage over the time period of 4 months. Patients with PEA usually recover without medication or surgical treatment within a few weeks. However, due to continuing bloating and irregular bowel movements we investigated carbohydrate malabsorption and diagnosed a fructose malabsorption. Bloating and irregular bowel movements in this patient with PEA were correlated to carbohydrate malabsorption and were treated successfully with a diet free of culprit carbohydrates.

Development of a novel osmotically driven drug delivery system for weakly basic drugs.

The drug substance SAG/ZK has a short biological half-life and because of its weakly basic nature a strong pH-dependent solubility was observed. The aim of this study was to develop a controlled release (cr) multiple unit pellet formulation for SAG/ZK with pH-independent drug release. Pellets with a drug load of 60% were prepared by extrusion/spheronization followed by cr-film coating with an extended release polyvinyl acetate/polyvinyl pyrrolidone dispersion (Kollidon SR 30 D). To overcome the problem of pH-dependent drug release the pellets were then coated with a second layer of an enteric methacrylic acid and ethyl acrylate copolymer (Kollicoat MAE 30 DP). To increase the drug release rates from the double layered cr-pellets different osmotically active ionic (sodium and potassium chloride) and nonionic (sucrose) additives were incorporated into the pellet core. Drug release studies were performed in media of different osmotic pressure to clarify the main release mechanism. Extended release coated pellets of SAG/ZK demonstrated pH-dependent drug release. Applying a second enteric coat on top of the extended release film coat failed in order to achieve pH-independent drug release. Already low enteric polymer levels on top of the extended release coated pellets decreased drug release rates at pH 1 drastically, thus resulting in a reversal of the pH-dependency (faster release at pH 6.8 than in 0.1N HCl). The addition of osmotically active ingredients (sodium and potassium chloride, and sucrose) increased the imbibing of aqueous fluids into the pellet cores thus providing a saturated drug solution inside the beads and increasing drug concentration gradients. In addition, for these pellets increased formation of pores and cracks in the polymer coating was observed. Hence drug release rates from double layered beads increased significantly. Therefore, pH-independent osmotically driven SAG/ZK release was achieved from pellets containing osmotically active ingredients and coated with an extended and enteric polymer. In contrast, with increasing osmotic pressure of the dissolution medium the in vitro drug release rates decreased significantly.

Development of a multiple unit pellet formulation for a weakly basic drug.

SAG/ZK [3-(5-Chloro-2-[2-[(2R)-4-(4-fluorobenzyl)-2-methylpiperazin-1-yl]-2-oxoethoxy]phenyl)uronium hydrogen sulfate], a potent candidate for the oral treatment of inflammatory diseases, demonstrated pH-dependent solubility. Drug release from conventional pellet formulations decreased with increasing pH values of the dissolution medium. The aim of this study was to overcome this problem and to achieve pH-independent drug release. Extended release pellets were prepared by extrusion/spheronization followed by film coating with an aqueous polyvinylacetate/polyvinylpyrrolidone dispersion. To overcome the problem of pH-dependent drug release organic acids such as fumaric, tartaric, and adipic acid were incorporated into the core pellets. X-ray diffraction studies were done in order to investigate potential recrystallization and formation of different salts of SAG/ZK. The addition of fumaric acid was found to lower the pH values within the core pellets during the release of SAG/ZK in phosphate buffer pH 6.8. Therefore, increased release rates at higher pH values were observed thus leading to pH-independent drug release. In contrast, drug release remained pH-dependent for pellets containing tartaric and adipic acid, which can be explained with the lower acidic strength and higher aqueous solubility of these acids. X-ray diffraction studies showed no recrystallization and formation of salts of active ingredient and organic acid.

Somatostatin receptor scintigraphy in patients with cat-scratch disease.

AIM: Somatostatin receptor scintigraphy images various neoplastic, granulomatous, and auto-immune diseases. Cat-scratch disease in an infectious granulomatous disease usually affecting the lymphnodes. It is not known whether cat-scratch disease provides positive somatostatin receptor scintigrams. PATIENTS, METHODS: Twelve patients with lymphadenitis and suspected cat-scratch disease were investigated by immunofluorescence antibody testing and somatostatin receptor scintigraphy. Suppurated lymphnodes were extracted or drained and Bartonella henselae specific PCR was then performed. RESULTS: Eleven of 12 patients showed IgG antibodies against B. henselae. SRS showed positive scintigraphic results in 6 of 11 patients with CSD. B. henselae DNA was detected in tissue of lymphnodes from 4 of 5 patients with lymphnode extraction or lymphnode drainage. SRS demonstrated positive scintigrams in all patients with a positive PCR. In one patient with suspected CSD SRS was negative as well as antibody testing. CONCLUSION: Somatostatin receptor scintigraphy correlated with positive Bartonella henselae specific PCR tests and positive Bartonella henselae specific antibody tests in patients with CSD.

Development of a single unit extended release formulation for ZK 811 752, a weakly basic drug.

ZK 811 752, a potent candidate for the treatment of autoimmune diseases, demonstrated pH-dependent solubility. The resulting release from conventional matrix tablets decreased with increasing pH-values of the dissolution medium. The aim of this study was to overcome this problem and to achieve pH-independent drug release. Three different polymers were used as matrix formers, the partly water-soluble and poorly swellable mixture of polyvinylacetate/polyvinylpyrrolidone, the water-insoluble and almost unswellable ethylcellulose (EC) and the water-soluble and highly swellable hydroxypropyl methylcellulose (HPMC). To solve the problem of pH-dependent solubility different organic acids, such as fumaric, tartaric, adipic, glutaric and sorbic acid were added to the drug-polymer system. The addition of organic acids to all three matrix formers was found to maintain low pH-values within the tablets during release of ZK 811 752 in phosphate buffer pH 6.8. Thus, the micro-environmental conditions for the dissolution of the weakly basic drug were kept almost constant. An extended release matrix tablet for ZK 811 752 consisting of drug, polymer and organic acid providing the desired pH-independent drug release has been developed.

Effects of lactulose and polyethylene glycol on colonic transit.

BACKGROUND: The effects of lactulose and polyethylene glycol on colonic transit are poorly established. AIM: To assess the effects of these laxatives on colonic transit in normal subjects. METHODS: Colonic transit (mean residence time, cumulative counts in stool, counts remaining in the proximal or distal colon) was measured scintigraphically in normal subjects on the second and third day of a 3-day ingestion of 67-134 g/day lactulose, or 59 g/day polyethylene glycol. RESULTS: At similar stool weight (lactulose: 653 +/- 120 g/day; polyethylene glycol: 522 +/- 66 g/day), transit was significantly slower during 99 g/day lactulose when compared with 59 g/day polyethylene glycol; this was most pronounced in the distal colon (mean residence time: lactulose - 403 +/- 55 min; polyethylene glycol - 160 +/- 41.9 min). Short chain fatty acid concentration in 24-h stool correlated significantly with counts remaining in the distal colon at 12 h (r = 0.79, P = 0.001). Increasing lactulose doses were significantly associated with increasing stool weight (r = 0.79) and shorter mean residence time in the total (r = -0.56) and distal colon (r = -0.64). The sum of faecal carbohydrates plus short chain fatty acids was associated with stool weight (r = 0.95, P < 0.001). CONCLUSION: Lactulose accelerates colonic transit. However, compared with polyethylene glycol, transit during lactulose is prolonged.

The role of 2-18F-fluoro-2-deoxy-D-glucose positron emission tomography in the diagnosis of giant cell arteritis of the temporal arteries.

OBJECTIVE: As one of the diagnostic criteria for giant cell arteritis affecting the temporal arteries (temporal arteritis) is still biopsy-proven vasculitis of the affected artery, the aim of our study was to evaluate the value of a non-invasive procedure, 2-(18)F-fluoro-2-deoxy-d-glucose (FDG) positron emission tomography (F-18-FDG-PET), in the diagnosis of Horton's disease. METHODS: During a period of 10 months, 22 consecutive patients with the clinical diagnosis of giant cell arteritis and a positive hypoechogenic halo in duplex sonography were re-examined with F-18-FDG-PET. Six patients had giant cell arteritis involving both the large arteries and the temporal arteries; five patients showed giant cell arteritis only in the large arteries without concomitant involvement of the temporal arteries, and the remaining 11 patients showed only involvement of the temporal arteries. All patients were examined by sonography and F-18-FDG-PET, which was performed before treatment with corticosteroids. RESULTS: All patients with positive signs of giant cell arteritis in duplex sonography, i.e. a hypoechogenic halo in the large arteries (thoracic, subclavian, axillary, iliac, aorta), also showed elevated FDG uptake in the same vessels, with complete agreement in the anatomical distribution of changes. When positive sonography was limited to the temporal arteries, FDG-PET was completely negative in the temporal arteries and all other arterial locations. CONCLUSION: PET is not yet suitable for the diagnosis of temporal arteritis and therefore cannot replace invasive biopsy. F-18-FDG-PET is well suited to the demonstration of giant cell arteritis in arteries exceeding 4 mm in diameter.

Silent haemoglobin variants and determination of HbA(1c) with the HPLC Bio-Rad Variant II.

AIMS: To evaluate the determination of HbA(1c) with an automated high performance liquid chromatography (HPLC) method in patients with clinically silent haemoglobin variants. METHODS: HbA(1c) values were determined with the ion exchange HPL Bio-Rad Variant II using the high resolution beta thalassaemia programme in patients with silent haemoglobin variants, namely: Hb Graz, Hb Sherwood Forest, Hb O Padova, and Hb D. RESULTS: All of these haemoglobin variants caused additional peaks in the chromatograms. No clinically useful HbA(1c) results were produced for patients with Hb Graz and Hb Sherwood Forest, the results for the patient with Hb D were too low, but the results for patients with Hb O Padova were acceptable. CONCLUSIONS: The development of this automated HPLC method modification with high resolution mode aids the identification of interference caused by the described clinically silent haemoglobin variants in HbA(1c) determination.

Hemoglobin variants and determination of glycated hemoglobin (HbA1c).

Measurement of glycated hemoglobin in diabetic patients is an established procedure for evaluating long-term control of diabetes. The Diabetes Control and Complications Trial (DCCT), as well as the United Kingdom Prospective Diabetes Study (UKPDS), confirmed the direct relationship between the degree of glycemic control as estimated by glycohemoglobin (GHb) determinations and the development and progression of long-term complications in diabetic patients. Samples with known interferences of HbA(1c) determination as hemoglobinopathies are specifically excluded from certification testing and there are no guidelines or requirements for comparability of samples containing hemoglobin (Hb) variants. This paper reviews the interference of Hb variants on determination methods of glycated hemoglobin as they result in false HbA(1c) results.