Production and separation of positron emitters for hadron therapy at FRS-Cave M.

The FRagment Separator FRS at GSI is a versatile spectrometer and separator for experiments with relativistic in-flight separated short-lived exotic beams. One branch of the FRS is connected to the target hall where the bio-medical cave (Cave M) is located. Recently a joint activity between the experimental groups of the FRS and the biophysics at the GSI and Department of physics at LMU was started to perform biomedical experiments relevant for hadron therapy with positron emitting carbon and oxygen beams. This paper presents the new ion-optical mode and commissioning results of the FRS-Cave M branch where positron emitting 15O-ions were provided to the medical cave for the first time. An overall conversion efficiency of 2.9±0.2×10-4 15O fragments per primary 16O ion accelerated in the synchrotron SIS18 was reached.

Imaging of brain metastases of bronchial carcinomas with 7 T MRI - initial results.

PURPOSE: To compare the depiction of brain metastases of bronchial carcinomas on susceptibility-weighted and contrast-enhanced images with 7 T and at 1.5 T MRI. MATERIALS AND METHODS: Twelve patients with brain metastases of bronchial carcinomas underwent 7 T and 1.5 T MRI. Minimum intensity projections (MinIP) of a 1.5 T SWI sequence (voxel size = 0.9 x 0.9 x 2.0 mm(3)) were compared to 7 T SWI MinIPs (voxel size = 0.4 x 0.4 x 1.5 mm(3)). A T 1-w 3D MPRAGE at 1.5 T (voxel size = 1 x 1 x 1 mm(3) after double-dose (DD) gadoterate meglumine, Gd-DOTA) was compared to a 7 T MPRAGE sequence (voxel size = 0.7 x 0.7 x x 0.7 mm(3), single dose (SD) Gd-DOTA) in all patients, and to DD Gd-DOTA in 6 patients after a 10 minute delay. The number of intracranial microhemorrhages in SWI MinIPs and the number of contrast-enhancing metastases in MPRAGE images were compared in each patient grouped into three size ranges (< or = 2 mm, > 2 mm and < 6 mm, > or = 6 mm) by two radiologists in consensus. RESULTS: In all 12 patients the 7 T SWI with spatially higher resolution allowed the identification of 87 versus 67 cerebral microhemorrhages at 1.5 T. 7 T T 1-w images after SD Gd-DOTA depicted 198 brain metastases versus 238 at 1.5 T after DD Gd-DOTA. After doubling the contrast dose in six patients, 4 additional brain metastases were identified at 7 T. CONCLUSION: Our preliminary results indicate that despite the higher spatial resolution the detection of brain metastases on 7 T MPRAGE images is almost equal to 1.5 T MPRAGE images. The 7 T SWI sequence with spatially higher resolution allowed the detection of 20 % more microhemorrhages in brain metastases compared to the 1.5 T SWI sequence.

Anthracyline-reduced sequential combination chemotherapy for younger patients with good-prognosis aggressive B-cell non-Hodgkin's lymphoma.

INTRODUCTION: Anthracyline-based chemotherapy is the treatment of choice for patients with aggressive B-cell non-Hodgkin's lymphoma (NHL). However, anthracyclines have been associated with long-term cardiac toxicity. METHODS: We conducted a study using a sequential combination chemotherapy with a reduced cumulative dose of anthracyclines in younger patients with good-prognosis aggressive NHL. Chemotherapy consisted of one cycle of vincristine, ifosfamide, etoposide, and dexamethasone, followed by three cycles of epirubicin, cyclophosphamide, vincristine, and dexamethasone, and a fifth cycle containing carboplatin, etoposide, and dexamethasone. 86 patients were treated, 65 without and 21 with additional rituximab. Consolidating involved-field irradiation was applied in patients with stage I/II, bulky disease, or localized residual lymphoma. RESULTS: Complete and partial remissions were achieved in 67 and 27% of patients, respectively, and the 3-year event-free and overall survival estimates were 75 and 87%. The survival estimates were substantially better in patients who received rituximab. Main toxicity was grade 3/4 leukocytopenia in 89% patients with neutropenic fever in 30%. Two patients died of septic shock. CONCLUSION: The treatment appears to be effective in this group of patients. The hematological toxicities, particularly after the first and fifth cycle, require the use of G-CSF and/or a dose reduction in selected patients.

Ifosfamide, etoposide, cytarabine, and dexamethasone as salvage treatment followed by high-dose cyclophosphamide, melphalan, and etoposide with autologous peripheral blood stem cell transplantation for relapsed or refractory lymphomas.

High-dose chemotherapy (HD-CT) with autologous stem cell transplantation is considered to be the treatment of choice for relapsed high-grade non-Hodgkin's lymphoma (NHL) and Hodgkin's lymphoma (HL) patients, but the optimal treatment has not yet been defined. We evaluated a salvage treatment regimen consisting of conventional cycles with ifosfamide, etoposide, cytarabine, and dexamethasone (IVAD) followed by two cycles of HD-CT consisting of cyclophosphamide, melphalan, and etoposide (CMV) with autologous stem cell support in patients with relapsed or refractory NHL (n = 59) and HL (n = 16). Response to IVAD was complete remission (CR) in 16 patients (21%), partial remission (PR) in 39 patients (52%), stable disease (SD) in 18 patients (24%), and progressive disease (PD) in two patients (2.7%). Of 70 patients treated with HD-CT, 41 patients (59%) showed a CR, 20 patients a PR (29%), eight patients a SD (11%), and one patient a PD (1.4%). The 5-yr overall survival for the entire group of patients was 29%, and for patients with NHL and HL 25%, and 38%, respectively. The respective event-free survival probabilities at 5 yr were 22%, 16%, and 31%. Seven treatment-related deaths due to septicemia (three), cardiac arrhythmia (one), pneumonia (one), pneumonitis (one), and toxic epidermal necrolysis (one) were observed. In multivariate analysis, an International Prognostic Index of > or = 2 and resistant disease to first-line chemotherapy were poor independent prognostic factors for the subgroup of patients with NHL. In conclusion, these results indicate that IVAD/CMV is feasible as a salvage therapy for lymphoma patients. This treatment is currently evaluated with the addition of rituximab.

Caspofungin treatment in severely ill, immunocompromised patients: a case-documentation study of 118 patients.

BACKGROUND: Caspofungin has shown efficacy in empirical antifungal therapy in neutropenic patients, refractory invasive Aspergillus infections and invasive candidiasis. Here we report the currently largest series of patients treated with caspofungin outside clinical trials. METHODS: Centres in Germany that were known to treat patients with invasive fungal infections were asked to fill out detailed questionnaires for all patients treated with caspofungin. No effort was made to influence the decision to use caspofungin. RESULTS: A total of 118 patients were evaluable (median age 48 years, interquartile range 38-58), out of which 41 (35%) suffered from acute leukaemia, 31 (26%) had allogeneic stem cell transplants, 16 (14%) lymphoma or myeloma, 8 (7%) autologous stem cell transplants and 22 (19%) other causes for immunosuppression. One hundred and six patients were evaluable for efficacy out of which 68 (64%) patients achieved a complete or partial remission. A total of 81 out of 115 (70%) patients were alive 30 days after the end of caspofungin therapy. Response rates were similar in proven (20/32, 63%) and probable (27/46, 59%) infections, in neutropenic patients (41/55, 75%) and in patients who were (44/70, 63%) or were not (24/36, 67%) refractory to antifungal pre-treatment. The response rate in mechanically ventilated patients was 29% (7/24). Caspofungin was well tolerated, even in 14 patients, who were concomitantly treated with ciclosporin A, no drug-related elevations of bilirubin, alanine aminotransferase or creatinine were found. CONCLUSIONS: This open case study of severely ill patients with invasive fungal infections demonstrates both excellent efficacy and very low toxicity of caspofungin.

Hemolytic uremic syndrome following prolonged gemcitabine therapy: report of four cases from a single institution.

Hemolytic uremic syndrome (HUS) has been described following the administration of multiple antineoplastic agents, most notably mitomycin C. More recently, several cases of gemcitabine-induced HUS have been observed with the overall incidence of gemcitabine-induced HUS estimated at 0.015-0.25%. We here report on four patients who developed HUS following gemcitabine therapy at our institution within the last year (incidence 1.4%). All these patients had advanced-stage disease, were heavily pretreated, and received prolonged gemcitabine application, suggesting that in this subgroup of patients HUS may be more frequently encountered than documented so far.

Thalidomide in combination with vincristine, epirubicin and dexamethasone (VED) for previously untreated patients with multiple myeloma.

The present study aimed to evaluate the side-effects and efficacy of thalidomide in combination with an anthracycline-containing chemotherapy regimen in previously untreated myeloma patients. Thalidomide (400 mg/d) was combined with bolus injections of vincristine and epirubicin and oral dexamethasone (VED). Chemotherapy cycles were repeated every 3 wk until no further reduction in myeloma protein was observed, whereas the treatment with thalidomide was continued until disease progression. Thirty-one patients were enrolled, 12 patients were exclusively treated with thalidomide in combination with VED and 19 patients additionally received high-dose melphalan, for consolidation. Adverse events and response to therapy were assessed prior to treatment with high-dose chemotherapy. Response to thalidomide combined with VED was complete remission in six patients (19%), partial remission in 19 patients (61%), stable disease in five patients (16%), and progressive disease in one patient (3.2%). Grade 3 and 4 adverse events consisted of leukocytopenia in 10 patients (32%), and thrombocytopenia and anemia in one patient each (3.2%). Neutropenic infections grade 3 and 4 occurred in seven (23%) and three patients (9.7%), respectively, including two patients (6.5%) who died from septic shock. Deep vein thrombosis occurred in eight patients (26%), constipation in 20 patients (65%), and polyneuropathy in 20 patients (65%). The probability of event-free survival and overall survival in the whole group of patients at 36 months were 26 and 62%, respectively. In conclusion, the combination of thalidomide with VED appears to be highly effective in previously untreated patients with multiple myeloma, but it is associated with a high rate of thrombotic events, polyneuropathy, and neutropenic infections.

FDG-PET/CT in re-staging of patients with lymphoma.

The aim of this study was to evaluate the clinical significance of combined fluorine-18 fluorodeoxyglucose positron emission tomography and computed tomography (FDG-PET/CT) in patients with lymphoma, and to compare the FDG-PET/CT staging results with those of FDG-PET and CT alone. Twenty-seven patients were studied. Each patient had clinical follow-up for >12 months and entered complete follow-up evaluation. Patient-based evaluation showed a sensitivity of 78% for CT alone, 86% for FDG-PET alone, 93% for CT and FDG-PET read side by side, and 93% for combined FDG-PET/CT imaging. Region-based evaluation showed a sensitivity for regional lymph node involvement of 61%, 78%, 91% and 96% respectively. FDG-PET/CT imaging is superior to CT alone ( P=0.02) and has additional benefit over FDG-PET alone due to exact anatomical localisation. We conclude that FDG-PET/CT imaging is accurate in re-staging lymphoma and offers advantages over separate FDG-PET and CT imaging.

First observation of self-amplified spontaneous emission in a free-electron laser at 109 nm wavelength

We present the first observation of self-amplified spontaneous emission (SASE) in a free-electron laser (FEL) in the vacuum ultraviolet regime at 109 nm wavelength (11 eV). The observed free-electron laser gain (approximately 3000) and the radiation characteristics, such as dependency on bunch charge, angular distribution, spectral width, and intensity fluctuations, are all consistent with the present models for SASE FELs.

Refractory period impairment in sural nerves of diabetics.

Polyneuropathy is a frequent complication in diabetics. In a non-selected group of 65 diabetics, 30 patients had clinical signs of neuropathy. These patients had more significant changes in electrophysiological parameters than patients without clinically evident polyneuropathy. Significant reduction of sural nerve conduction velocity was observed in 16 of 30 patients with and in 4 of 35 diabetics without clinical signs of polyneuropathy. Additional information was obtained when paired stimuli were applied and the test response latency was measured. Stimulus intervals of 3 ms gave the highest quota of information about involvement of the sural nerve. Significant prolongation of the test response in paired stimulation at intervals of 3 ms was found in 21 of 30 patients with clinically apparent diabetic polyneuropathy and in 16 of 35 diabetics without clinical signs of polyneuropathy.

[Principles of the automatic analysis of amplitude, transmission time, conduction velocity and refractory period of the compound nerve action potential of peripheral nerves. Results in the human sural nerve (author's transl)]. / Zum Prinzip der automatischen Bestimmung von Amplitude, Leitungsgeschwindigkeit, Laufzeitlatenz und Refraktärperiode des Summenaktionspotentials peripherer Nerven. Ergebnisse am N. suralis des Menschen.

A method for the automatical determination of the amplitude, the transmission time, the conduction velocity and the refractory period of sural nerve was evaluated by help of HISTOMAT-S/MULTI 20 computer. The results of the automatical analysis were compared with those of the conventional method in 50 healthy control persons. There was no significant difference between the dates. Accuracy and correctness were exactly in the same range, but the investigation time of the analysis by help of a computer is much shorter.

Sural nerve conduction velocity and refractory period in diabetics without clinical signs of neuropathy.

Twentysix patients aged 22-76 years with a duration of diabetes of 1 month to 23 years but without signs of symptoms of a peripheral nerve disease were studied. The nerve conduction velocity, the amplitude of the compound action potential and its restitution during the relative refractory period were examined in sural nerves. Nerve conduction velocity of the motor fibers were determined in the median, ulnar, tibial, and peroneal nerves. A reduced conduction velocity in motor nerves of the lower extremities were found in 10%, a reduced sensory nerve conduction velocity in 25%, and pathological changes of the refractory period in 50% of the patients. It is concluded that the determination of the relative refractory period can be used as a sensitive test in the early diagnosis of diabetic neuropathy.

Peripheral neuropathy and ophthalmologic toxicity after treatment with cis-dichlorodiaminoplatinum II.

A 57-year-old woman with inoperable bladder cancer received radiation treatment. Thirteen years later she relapsed at locoregional, retroperitoneal, and mediastinal sites. During treatment with cis-dichlorodiamineplatinum II (DDP) (30 mg/day for 5 days repeated every 4 weeks) she achieved a partial remission. After seven courses of DDP-chemotherapy she complained of numbness of her hands and legs and of diminished visual acuity of both eyes. After 4 weeks these symptoms grew less but intensified severely after another DDP-treatment. The temporal relationship of neurologic symptoms and their intensification by the last administration of DDP suggest this drug to be the causative agent for peripheral neuropathy and ophthalmologic toxicity.

[Reversible alterations of peripheral nerve function in thyroid dysfunction (author's transl)]. / Reversible Funktionsstörungen peripherer Nerven bei Patienten mit Schilddrüsenerkrankungen.

In 7 patients with hyperthyroidism and 9 patients with hypothyroidism both thve before treatment and after a period of normal thyroid function of at least one year duration. As far as conduction velocity and relative refractory period are concerned there was no difference between hyperthyroid patients and normal persons, whereas in cases of hypothyroidism before treatment the conduction velocity was shown to be significantly reduced; moreover a prolonged relative refractory period and a decline in amplitude of the nerve action potential were found. These alterations of peripheral nerve function, interpreted as evidence of neuropathy, proved to be reversible when the thyroid function returned to normal.

Refractory period of human sural nerve action potential related to age in healthy probands.

150 sural nerves from 150 probands 10-70 years of age were investigated by applying supramaximal paired electric stimuli and recording the action potentials with needle electrodes. The responses to the first and second stimulus were evaluated with respect to latency and amplitude. Correlation of the electrophysiological findings with the age of the probands gave the following results: (1) Slight but statistical insignificant reduction of conduction velocity with advancing age up to 70 years. (2) Statistical significant decrease of amplitudes and prolongation of potential duration with advancing age. (3) No significant relationship between refractory period (latency and amplitude of the test response) and advancing age up to 70 years. The results are discussed in terms of their clinical meaning.