EURAMOS-1, an international randomised study for osteosarcoma: results from pre-randomisation treatment.

BACKGROUND: Four international study groups undertook a large study in resectable osteosarcoma, which included two randomised controlled trials, to determine the effect on survival of changing post-operative chemotherapy based on histological response. PATIENTS AND METHODS: Patients with resectable osteosarcoma aged ≤40 years were treated with the MAP regimen, comprising pre-operatively of two 5-week cycles of cisplatin 120 mg/m(2), doxorubicin 75 mg/m(2), methotrexate 12 g/m(2) × 2 (MAP) and post-operatively two further cycles of MAP and two cycles of just MA. Patients were randomised after surgery. Those with ≥10% viable tumour in the resected specimen received MAP or MAP with ifosfamide and etoposide. Those with <10% viable tumour were allocated to MAP or MAP followed by pegylated interferon. Longitudinal evaluation of quality of life was undertaken. RESULTS: Recruitment was completed to the largest osteosarcoma study to date in 75 months. Commencing March 2005, 2260 patients were registered from 326 centres across 17 countries. About 1334 of 2260 registered patients (59%) were randomised. Pre-operative chemotherapy was completed according to protocol in 94%. Grade 3-4 neutropenia affected 83% of cycles and 59% were complicated by infection. There were three (0.13%) deaths related to pre-operative chemotherapy. At definitive surgery, 50% of patients had at least 90% necrosis in the resected specimen. CONCLUSIONS: New models of collaboration are required to successfully conduct trials to improve outcomes of patients with rare cancers; EURAMOS-1 demonstrates achievability. Considerable regulatory, financial and operational challenges must be overcome to develop similar studies in the future. The trial is registered as NCT00134030 and ISRCTN 67613327.

Effectiveness of Rex shunt in children with portal hypertension following liver transplantation or with primary portal hypertension.

Portal vein thrombosis can occur as a result of primary anomalies, after liver transplantation, and for other reasons. It may result in severe complications secondary to portal hypertension, such as bleeding from esophageal or gastric varices, hypersplenism, or impaired somatic growth. In this retrospective study, we analyzed the outcome of 25 children who underwent a Rex shunt procedure. The following venous grafts were used as the shunt: the autologous internal or external jugular vein (n = 17) or a cryopreserved graft (n = 5); in three patients the umbilical vein was recanalized. The median follow up time was 109 months (range 18 days-146 months). The best results were achieved in patients in whom an autologous jugular vein segment was used as a vascular graft for the Rex shunt (shunt patency of 88%). In patients with a functioning shunt no further lower or upper gastrointestinal bleeding occurred. And in the entire study population hypersplenism syndrome improved after surgery. In our large cohort of pediatric patients, the Rex shunt has shown to be an effective method to eliminate portal hypertension and to revascularize the liver and thereby prevents the possible consequences of long-term portosystemic shunting.

Intraoperative anisocoria in a child during renal transplantation.

Anisocoria during anaesthesia may indicate a serious neurological condition. Assessment by physical examination and diagnostic imaging is limited during surgery and anaesthesia. We report a case of a boy undergoing renal transplantation, who suffered from anisocoria during general anaesthesia. A transcranial sonography was performed, showing no intracranial pathology. However, retinal hypoperfusion detected with orbital doppler sonography was a plausible explanation for anisocoria.

[Severe accidental hypothermia with cardiac arrest and extracorporeal rewarming. A case report of a 2-year-old child]. / Schwere akzidentelle Hypothermie mit Kreislaufstillstand und extrakorporaler Erwärmung. Fallbericht eines 2-jährigen Kindes.

In patients with severe hypothermia and cardiac arrest, active rewarming is recommended by extracorporeal circulation with cardiopulmonary bypass. The current guidelines for resuscitation of the European Resuscitation Council now include the recommendation regarding patients with hypothermia remaining comatose after initial resuscitation to accomplish an active rewarming only up to a temperature of 32-34 degrees C and to maintain a mild hypothermia for 12-24 h. We report the case of a 2-year-old boy who suffered from severe hypothermia after falling into ice-cold water. On discovery cardiac arrest with asystole was present and the first measured temperature was 23.8 degrees C. Resuscitation led to restoration of spontaneous circulation. The patient was rewarmed by extracorporeal circulation with cardiopulmonary bypass to 33 degrees C then mild hypothermia was maintained for a further 12 h. On the third day after the accident the patient was extubated and after a further 9 days was discharged without any sequelae.

[Extrahepatic cholestasia during therapy with Zolmitriptan (AscoTop)]. / Extrahepatische Cholestase unter Therapie mit Zolmitriptan (Asco-Top).

Because of recurrent abdominal pain, jaundice and elevated liver function tests, a sixty-two-year old man had been referred to hospital several times within the preceding six months. By means of ultrasonography, endoscopic retrograde cholangiopancreatography (ERCP) and magnetic resonant cholangiopancreatography, dilated extrahepatic bile ducts were diagnosed. Stones and a tumorous process were excluded. ERCP showed hypermotility of the upper gastrointestinal tract. Quantitative hepatobiliary scintigraphy demonstrated retention of activity in the intra- and extrahepatic bile ducts and delayed transit of activity to the duodenum as signs of papillary dysfunction. Drug anamnesis revealed that the patient had started migraine treatment with Zolmitiptan, a 5-HT (1B/1D)-receptor agonist of the second generation, six months before the beginning of the cholestasia syndrome. Because of the known increase in amplitudes of oesophageal motor waves and of lower oesophageal sphincter tone by Sumatriptan, a 5-HT (1B/1D)-receptor agonist of the first generation, Zolmitriptan treatment was stopped. Thereupon, laboratory findings normalised and the patient has been feeling well for more than one year. Serotonin is an important monamine neurotransmitter that acts both in the CNS and in the gastrointestinal tract on identical receptors and is transported by the same systems. Thus it is not surprising that therapeutic measures which influence the serotoninergic system in the CNS are also effective in the enteric nervous.

Diagnostic and clinical value of anti-cyclic citrullinated peptide antibodies compared with rheumatoid factor isotypes in rheumatoid arthritis.

OBJECTIVE: To assess the additional diagnostic and clinical value of the second test generation of anti-cyclic citrullinated peptide antibodies (CCP2) compared with rheumatoid factor isotypes (IgG-RF, IgA-RF, IgM-RF) in patients with rheumatoid arthritis. METHODS: This was a prospective study on 715 patients: rheumatoid arthritis (n = 295), degenerative or other inflammatory joint disease (n = 163), connective tissue disease or vasculitis (n = 103), and healthy controls (n = 154). Sera from each subject were tested for CCP2 and RF isotypes by enzyme linked immunosorbent assay (ELISA). Agreement with clinical indices such as disease activity, joint destruction, disease duration, and other laboratory tests was assessed. Sensitivity and specificity of the tests were evaluated taking the clinical diagnosis as the gold standard. RESULTS: Highest sensitivity was found for IgM-RF (66.4%) and CCP (64.4%). Highest specificity was achieved by CCP (97.1%) and IgG-RF (91.0%). In rheumatoid patients with high disease activity or severe joint damage, CCP was more often present (81.4% and 83.6%) than all RF isotypes. Of special diagnostic value was the detection of positive CCP in 34.5% of all patients with rheumatoid arthritis when all measured RF isotypes (IgG-RF, IgA-RF, and IgM-RF) were negative. CONCLUSIONS: As a screening method for rheumatoid arthritis the IgM-RF and the CCP assays are superior to other RF isotypes. Positivity in the highly specific CCP ELISA supports the diagnosis of rheumatoid arthritis. CCP proved to be a powerful diagnostic tool, especially in ambiguous cases or RF negative patients with rheumatoid arthritis.

Clinical significance of anti-dsDNA antibody isotypes: IgG/IgM ratio of anti-dsDNA antibodies as a prognostic marker for lupus nephritis.

The objective of this paper is to investigate the association between patterns of anti-dsDNA antibody isotypes and specific clinical manifestations (categorized in renal, musculoskeletal, cutaneous, hematological, pulmonary, neurological and cardiac). Sera of 202 systemic lupus erythematosus (SLE) patients, 33 patients suffering from other autoimmune diseases and 115 healthy blood donors were analysed for anti-dsDNA antibodies by IgG-, IgA- and IgM-specific ELISA, Farr-assay and CLIF. A subset of 24 SLE patients was investigated in a longitudinal study over a period of one to six years. Disease activity of 105 SLE patients was measured according to the ECLAM score. In the cohort of SLE patients 63% were positive for the IgG class, 40% for the IgA and 57% for the IgM class specific anti-dsDNA ELISA. Sensitivity (79%) and specificity (99%) for the diagnosis of SLE appeared to be highest for the ELISA measuring all isotypes of anti-dsDNA antibodies. The concentrations of anti-dsDNA isotypes showed a strong correlation with disease activity. Analysing the relationship between IgG, IgA and IgM anti-dsDNA antibody isotypes and clinical manifestation, we found a significant association of the IgM isotype with cutaneous involvement and of the IgG isotype with lupus nephritis. The IgG/IgM ratio of anti-dsDNA antibodies represented a significant parameter to distinguish patients with lupus nephritis from those without renal involvement. In the longitudinal study, a continuous ratio under 0.8 was associated with absence of renal involvement throughout the investigated period. In conclusion, the evaluation of anti-dsDNA isotypes provides a diagnostic tool to define subsets within SLE patients with different clinical manifestations. In particular, the IgG/IgM ratio of anti-dsDNA antibodies could be used as a prognostic marker for lupus nephritis during the course of the disease.

[Adult Still's disease as a manifestation of severe hypophosphatemia. Still's disease--a disturbance of energy metabolism?]. / Adultes Still-Syndrom als Manifestation einer schweren Hypophosphatämie. Morbus Still--eine Störung des Energiestoffwechsels?

In this case report, a 56-year-old woman with a reversible multiple organ disease with septic fever, arthritis, rash, weight loss, thrombocytopenia, severe disturbance of liver function, renal tubular dysfunction, general muscular weakness, pleural and pericardial effusions and elevated CRP, leukocytosis and a striking hyperferritinemia is presented. An autoimmune disease and a septic process were excluded. Because of the significantly decreased plasma phosphorus concentration (0.2 mmol/l), caused by malabsorption after Whipple's operation with lowered vitamin D and secondary hyperparathyroidism and by chronic alcoholism, severe phosphate deficiency was diagnosed. By substitution of phosphorus, all symptoms disappeared and laboratory findings normalized. Except for the patient's age, all criteria for the diagnosis of Still's disease were fulfilled. So we reflected upon Still's disease to be rather a disturbance of energy metabolism with secondary immunologic changes than an inflammatory rheumatic disease. Significant weight loss in Still's disease and osteopenia might be signs of decreased energy supply. Besides hypophosphatemia, deficiency of magnesium, which is involved in all ATP-dependent processes, and mitochondrial diseases cause disturbances of energy metabolism.

In polymyalgia rheumatica serum prolactin is positively correlated with the number of typical symptoms but not with typical inflammatory markers.

OBJECTIVES: Hyperprolactinaemia has been associated with the active phase of human systemic lupus erythematosus and rheumatoid arthritis. In the present study, we investigated the role of prolactin (PRL) in relation to the number of typical symptoms and serum markers of systemic inflammation in patients with polymyalgia rheumatica (PMR). METHODS: One hundred and two PMR patients presented with typical symptoms such as adynamia, bilateral muscular pain in shoulders, upper arms or neck, bilateral muscular pain in the pelvic girdle, headache, morning stiffness, arthralgia, symptoms of depression, fever, initial weight loss (>4 kg/month), and transient visual symptoms. If one of the mentioned symptoms was present, the corresponding item was scored with one point (maximum unweighted item points=10). PRL, interleukin-2 (IL-2), IL-6, IL-1 receptor antagonist (IL-1ra), tumour necrosis factor (TNF), soluble IL-2 receptor (sIL-2R), and soluble vascular cell adhesion molecule (sVCAM) were measured by enzyme-linked immunosorbent assay in patients and 31 age-matched healthy controls. RESULTS: Fifteen PMR patients with elevated PRL had a higher number of symptoms as compared with patients with normal levels (P=0.003). PRL was correlated with the number of symptoms (all PMR patients: r(rank)=+0.380, P<0.001) and duration of morning stiffness (all PMR patients: r(rank)=+0.335, P=0.002) irrespective of prior corticosteroid treatment. However, PRL did not correlate with markers of systemic inflammation such as erythrocyte sedimentation rate, C-reactive protein, serum IL-1ra, IL-2, sIL-2R, IL-6, TNF, and sVCAM. CONCLUSION: The number of symptoms in PMR patients was positively correlated with PRL, but PRL was not correlated with serum markers of inflammation. This indicates that PRL is not a pro-inflammatory stimulus in patients with PMR. The inter-relationship between PRL and symptoms or duration of morning stiffness may be more a sign of central nervous system involvement, as it can be observed in people with depressed mood or under psychological stress.

Is there still a need for living-related liver transplantation in children?

OBJECTIVE: To assess and compare the value of split-liver transplantation (SLT) and living-related liver transplantation (LRT). SUMMARY BACKGROUND DATA: The concept of SLT results from the development of reduced-size transplantation. A further development of SLT, the in situ split technique, is derived from LRT, which itself marks the optimized outcome in terms of postoperative graft function and survival. The combination of SLT and LRT has abolished deaths on the waiting list, thus raising the question whether living donor liver transplantation is still necessary. METHODS: Outcomes and postoperative liver function of 43 primary LRT patients were compared with those of 49 primary SLT patients (14 ex situ, 35 in situ) with known graft weight performed between April 1996 and December 2000. Survival rates were analyzed using the Kaplan-Meier method. RESULTS: After a median follow-up of 35 months, actual patient survival rates were 82% in the SLT group and 88% in the LRT group. Actual graft survival rates were 76% and 81%, respectively. The incidence of primary nonfunction was 12% in the SLT group and 2.3% in the LRT group. Liver function parameters (prothrombin time, factor V, bilirubin clearance) and surgical complication rates did not differ significantly. In the SLT group, mean cold ischemic time was longer than in the LRT group. Serum values of alanine aminotransferase during the first postoperative week were significantly higher in the SLT group. In the LRT group, there were more grafts with signs of fatty degeneration than in the SLT group. CONCLUSIONS: The short- and long-term outcomes after LRT and SLT did not differ significantly. To avoid the risk for the donor in LRT, SLT represents the first-line therapy in pediatric liver transplantation in countries where cadaveric organs are available. LRT provides a solution for urgent cases in which a cadaveric graft cannot be found in time or if the choice of the optimal time point for transplantation is vital.

Nasal glioma presenting as capillary haemangioma.

UNLABELLED: We report the case of a 5-month-old female infant with a congenital nasal tumour originally attributed to a capillary haemangioma. Doppler-flow ultrasound imaging revealed a solid mass surrounded by mildly enlarged vessels which had a flow pattern atypical of haemangioma. Histology showed non-malignant gliomatous cells with low proliferative activity. A diagnosis of nasal glioma was thus established and the patient underwent cranial MRT which excluded intracranial communication of the nasal glioma. Nasal gliomas arise from a skull defect, originating from the defective closure of the anterior neuroporus. They represent encephaloceles which have lost their intracranial connection. Nasal gliomas usually present shortly after birth as an intranasal obstruction or, as in our case, as a mostly extranasal tumour. CONCLUSION: Nasal glioma is often misdiagnosed as a capillary haemangioma. It can be distinguished from the latter by Doppler-flow ultrasonography. Magnetic resonance imaging is required to exclude intracranial communication.

Ultrasound-guided surgery of deep seated brain lesions.

OBJECTIVE: Computer aided navigation systems have been introduced to optimize the neurosurgical strategies minimizing the damage to the healthy brain tissue. As the loss of cerebrospinal fluid and surgical manipulation alter the position of the lesion in the external reference system, there is a risk of being misguided to deep seated brain tumors. In this context we present our experiences with intraoperative ultrasound which represents a real-time navigation system. PATIENTS AND METHODS: 45 patients with subcortical intracerebral lesions were operated on with the support of ultrasound imaging. Tumor depth from the surface measured 5 (superficial) to 68 mm. The minimum size of a cavernoma was 8 mm. Histopathological diagnoses included 17 cavernomas, 12 metastases and 16 gliomas. Ultrasound localization was achieved by two perpendicular projections and the surgical trajectory of the lesion secured by catheter placement. RESULTS: Intraoperative ultrasound allowed an easy identification of all brain lesions. Additionally, a reliable localization of the tumor margins, including gliomas and metastases, was reached in 23 of 28 (82%) cases. The remaining 17 cavernomas were located all by intraoperative ultrasound, even the deep seated brain lesions of less than 10 mm in diameter could be easily detected. The real-time mode enabled a control of the surgical procedure. Technical problems arose from irregular and vaulted cortex surface, head positioning and surgical manipulation causing air artefacts with distal reduction of the signal intensity. CONCLUSION: Intraoperative ultrasound is a reliable intraoperative guidance tool in the localization of deep seated brain tumors because it operates in real-time, thus increasing the safety of the surgical procedure and of the tumor resection.