Protroca: A Noninterventional Study on Prophylactic Lipegfilgrastim against Chemotherapy-Induced Neutropenia in Nonselected Breast Cancer Patients

BackgroundProtroca evaluated the efficacy and safety of primary and secondary prophylaxis of neutropenia with lipegfilgrastim (Lonquex®) in breast cancer patients receiving neoadjuvant or adjuvant chemotherapy (CT).Patients and MethodsOf the 255 patients enrolled, 248 patients were evaluable for the intent-to-treat (ITT) and 194 patients for the per-protocol set. Primary and secondary end points after lipegfilgrastim treatment were assessed.ResultsNine patients of the ITT set receiving lipegfilgrastim as primary prophylaxis (n = 222) had febrile neutropenia of grade 3–4 (5 patients) or infection of grade 3–4 (4 patients); 1/26 of those receiving secondary prophylaxis had an event. Dose reductions were performed in 9.5% of the patients. Postponement of cancer CT cycles for >3 days occurred in <15% of patients; 10.8% (92/851 AEs) and 8% (2/25 SAEs) of documented adverse events and serious adverse events, respectively, were related to lipegfilgrastim.ConclusionsApplication of lipegfilgrastim was effective as primary and secondary prophylaxis in the prevention of CT-induced neutropenia in breast cancer.     

Pb2+ modulates the NMDA-receptor-channel complex

Summary The actions of Pb²⁺ on NMDA channel currents of acutely dissociated hippocampal CA1- and CA3-neurones from adult rats activated by aspartate plus glycine (asp/gly) were examined. A fast reversible and a slow irreversible response to Pb²⁺ were found. Pb²⁺ applied simultaneously with asp/gly decreased an inward current. The threshold concentration was below 2 M, the current was reduced > 90% at concentrations over 100 M, The decrease of the asp/gly activated current showed no voltage dependence. Opening of NMDA channels was not necessary for Pb²⁺-action, as preincubation in 50 M Pb²⁺-containing external solution for several seconds dramatically reduced the response to asp/gly/Pb²⁺. This effect was reversed within 2 to 5 s of wash. Presence of Pb²⁺ or asp/Pb²⁺ or glycine/Pb²⁺ in the external solution did not prevent recovery of the NMDA receptor/channel complex from desensitization. Prolonged perfusion of a cell with the asp/gly/Pb²⁺-containing external solution resulted in an irreversible decrease of the asp/gly current, whereas the amplitude of the asp/gly/Pb²⁺ response did not change over the duration of an experiment. We conclude that Pb²⁺ modulates NMDA channel activity via interaction with the NMDA/glycine receptor: as a result the channel current decreases.Abbreviations NMDA N-methyl-D-aspartate - LTP long-term potentiation - AP5 2-amino-5-phosphonovalerate - EGTA ethylene glycol bis(-aminoethylether)-N,N,N,N-tetraacetic acid - HEPES 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid Correspondence to H. L. Haas at the above address     

Hippocampal loss of the GABAA receptor α1 subunit in patients with chronic pharmacoresistant epilepsies

Alterations of gamma aminobutyric acid (GABA)-mediated neurotransmission have been implicated in the pathogenesis of epilepsies. Here we examine the distribution of the GABA_A receptor in the hippocampus of 78 surgical specimens from patients with chronic pharmacoresistant focal epilepsies. The receptor was localized immunohistochemically with the monoclonal antibody bd-24 which selectively recognizes the ₁ subunit of the GABA_A receptor. The results were compared with the receptor distribution of 28 normal hippocampal specimens obtained at autopsy. In the great majority of the surgical specimens a loss of GABA_A receptor immunoreactivity was present in CA1 (92.3%), CA4 (78.2%), the dentate granular cell layer (70.5%) and the molecular layer of the dentate gyrus (65.4%). The subiculum revealed a normal staining pattern in all but 4 cases. In no instance did we observe an increase of immunoreactivity in any region or cell population. The decrease of GABA_A receptor immunoreactivity was closely related to neuronal loss in the respective specimen and to Ammon's horn sclerosis. There was no correlation between GABA_A receptor loss and the patient's age at surgery, duration of seizures, age at onset of seizures and to the presence or absence of secondary generalized tonic clonic seizures. The data suggest that the observed loss of GABA_A receptor immunoreactivity is a secondary phenomenon rather than an event that is relevant for the pathogenesis of epileptic seizures.     

Motor activity of rats following intracerebral injections of drugs influencing GABA mechanisms

Summary Motor activity of rats was recorded following bilateral injections of GABA and the two GABA analogues gammahydroxybutyric acid (GHBA) and baclofen into the nucleus accumbens. GABA produced a shortlasting hypoactivity and this effect was potentiated by the GABA transaminase inhibitor aminooxyacetic acid (AOAA). More pronounced hypoactivities were caused by GHBA and baclofen. The hypoactivity was followed by hyperactivity after GHBA, baclofen and, to a small extent, after AOAA plus GABA. Systemic treatment with GHBA and GABA also suppressed motor activity and GHBA caused a subsequent hyperactivity. Small doses of GABA and particularly GHBA injected into the nucleus accumbens caused an increase in motor activity without the preceding decrease, especially when the rats were habituated to the environment. The effects appeared specific since no or only small changes in motor activity were induced by carnitine and betahydroxybutyric acid, structurally related to GABA and GHBA, respectively. Furthermore, the motor activity was stimulated by local treatment with the GABA receptor blocking agent picrotoxin, but not by strychnine or pentylenetetrazole. GHBA and GABA inhibited the apomorphine-induced activity of reserpine-treated rats indicating that these compounds stimulate GABA receptors beyond the dopamine synapses. The motor activity was depressed by GHBA and GABA given into the rostral and intermediate neostriatum and into the globus pallidus and, to a smaller extent, when given into the caudal neostriatum. The stimulatory effect of GHBA or picrotoxin was less, pronounced after local application to the globus pallidus or the neostriatum than when applied to the nucleus accumbens. The increased motor activity by GHBA, baclofen and GABA might be due to stimulation of GABA autoreceptors in the nucleus accumbens. The decreased motor activity might be evoked by stimulation of postsynaptic GABA receptors in the nucleus accumbens but a similar action in the corpus striatum might contribute.Part of the data was presented at the symposium on Interactions Among Putative Transmitters in the Brain held at the Mario Negri Institute, Milan, Italy on October 26–28, 1976     

Contribution of thallium-201-SPECT to the grading of tumorous alterations of the brain

Single photon emission computed tomography (SPECT) with thallium-201-chloride (²⁰¹TI) was used in 22 patients to assess the grade of malignancy of brain tumors.Low- and high-grade malignant gliomas could be well differentiated by calculating the Grade Index (GI), i.e., ²⁰¹TI uptake in the tumor area relative to a contralateral brain region. Low-grade gliomas (WHO-grade I–II) usually showed a GI of <1.5. Tumors classified histologically as high-grade malignant (WHO-grade III–IV) had GI values greater than 1.42 and a mean value of 1.89.Until labelled amino-acid tracers for gamma-cameras become commercially available, thallium-201 brain-SPECT can provide an independent and complementary method to CT/MRI for the differential diagnosis of grading of brain tumors. This simple technique can help to reduce sampling errors during needle biopsies of brain tumors, particularly of high-grade lesions incorrectly graded as low-grade tumors due to inadequate biopsy material. In addition, pre- and post-therapy studies can influence the strategy of therapy itself and allow an early detection of recurrences.     

Kluger's “Fixateur interne” for spinal instability

Kluger's Fixateur Interne proved to be an excellent tool not only in spinal trauma for repositioning of impacted fractures and transpedicular stabilization of the dorsal column but also in other forms of thoracic or lumbar instability.After spinal tumor excision from a dorsal approach and vertebral replacement with methylmethacrylate additional stability through dorsal fixation was achieved with this device.Spondylodiscitis, symptomatic spondylolisthesis, spinal instability from degenerative disc disease as well as nonunion following previous surgery could be cured using Kluger's internal fixation. Rare complications, i.e. from broken screws or rods (5%) caused no problems, but some patients required a second operation for readjustment of malpositioned screws which were causing pain or neurological deficit.     

An in vitro model for videoimaging of human bladder smooth muscle cell contractions

Knowledge regarding human bladder smooth muscle cell (SMC) physiology is very limited. Only a few specific medical therapies for bladder disorders have therefore been established. The objective of this study was to develop a model for videomicroscopy of bladder SMC contractions. Cells were isolated from human cystoprostatectomy specimens and cultured in a modified EMEM medium. These cells were identified as SMCs by means of immunohistochemistry. For videomicroscopy, the culture flasks were coated with a viscous agent to allow cell contraction. Contractions were visualized by means of a cell culture microscope with a time-lapse videosystem. For cholinergic stimulation of the cells, acetylcholine, in concentrations ranging from 100 μM to 10 mM, was applied. The percentage of contracting cells within the observation field was evaluated for quantitative analysis. In control experiments without contractile stimulant 6% of the cells were observed to contract. Stimulation with acetylcholine induced a significant dose-dependent increase to 47% in contracting cells. These results demonstrated that videomicroscopy is an appropriate tool to investigate the contraction mechanisms of bladder SMCs. This model offers the possibility of studying drug effects on the human detrusor in vitro. Received: 16 September 1999 / Accepted: 1 May 2000     

Tierexperimentelle Beobachtungen über das intracerebrale Wachstum menschlicher Tumoren

Zusammenfassung Das Wachstumsverhalten zweier in das Gehirn von Goldhamstern implantierter menschlicher Tumoren (H. Ad. Nr. 1 und H. S. Nr. 1) wurde untersucht. Bei allen Tieren konnte ein Tumorwachstum histologisch nachgewiesen werden. Cortisonvorbehandlung der Wirtstiere begünstigte bei H. Ad. Nr. 1 die Tumorausbreitung und führte frühzeitiger zum Tode. Das intracerebrale Tumorwachstum führte jedoch auch unabhängig von der Wirtsvorbehandlung bei allen Tieren zum Tode innerhalb von 4 Wochen nach der Transplantation. Beide Geschwulst-typen wuchsen am besten in den liquorhaltigen Räumen, weniger in der Hirnsubstanz. Die Bevorzugung der Meningen durch beide Tumortypen entspricht der allgemeinen Erfahrung über die cerebrale Metastasierung entdifferenzierte Sarkome und Adenocarcinome.

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Summary The growth behavior of two human tumors (H. Ad. No. 1 and H. S. No. 1) transplanted to the hamster brain has been studied. Tumor growth could be histologically verified in all animals inoculated. Cortisone-conditioning of the host increased tumor expansion and resulted in an earlier and more rapid death rate in the H. Ad. No. 1 group. Regardless of tumor or host-conditioning employed, all animals succumbed to intracerebral tumor growth by the end of the fourth week post transplantation. Both tumor types grew better in the ventricles and subarachnoid space than in the brain tissue itself. The predilection of these two tumor types for the meninges confirms our clinical knowledge on the pattern of cerebral metastasis of dedifferentiated sarcomas and adenocarcinomas.

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Mit Unterstützung der Deutschen Forschungsgemeinschaft.