T. Weber

Staging of the mediastinum: value of positron emission tomography imaging in non-small cell lung cancer

Recent studies have shown limitations of morphological imaging in staging mediastinal lymph node involvement in lung cancer. In contrast to computed tomography (CT), which depends primarily on anatomical imaging features, positron emission tomography (PET) with 18-fluorodeoxyglucose (FDG) depends mainly on the metabolic characteristics of a tissue for the diagnosis of disease. We have performed a prospective study comparing FDG-PET and CT of the thorax in the presurgical assessment of the mediastinum in 50 patients with newly diagnosed non-small cell lung cancer (NSCLC). CT and PET scans were interpreted separately, and results were compared to pathological staging obtained during thoracotomy. Hilar or mediastinal lymph node involvement was present in 58%. In staging for lymph node involvement, CT had a sensitivity of 72% and specificity of 81%, whereas PET had a sensitivity and specificity of 90% and 86%, respectively. When the PET study was compared to histological results, there were four cases showing more advanced mediastinal involvement with PET and four cases showing less involvement with PET. From our preliminary results, we conclude that positron emission tomography with 18-fluorodeoxyglucose is significantly more accurate than computed tomography in the mediastinal staging of non-small cell lung cancer.

Neuronotrophic Effect of Developing Otic Vesicle on Cochleo-Vestibular Neurons: Evidence for Nerve Growth Factor Involvement

In the developing inner ear, the existence of a neuronal death and of a peripheral target-derived trophic effect on cochleovestibular neurons has been documented. Using cultures of rat cochleovestibular neurons, we show that the E12 otic vesicle releases a factor promoting the survival and the neuritogenesis of these neurons, and that this effect is mimicked by NGF. The effect of the optic vesicle conditioned medium (OVCM) on cochleovestibular neurons is suppressed by anti-NGF antibodies. OVCM is neuronotrophic for NGF-sensitive sympathetic neurons, an effect that is also suppressed by anti-NGF antibodies, further demonstrating the presence of biologically active nerve growth factor.

Growth Factor Interactions in Cultures of Dissociated Adult Acoustic Ganglia: Neuronotrophic Effects

Auditory neurons cultured from adult rat acoustic ganglia require for survival either a substrate bound factor(s) present in astrocyte conditioned medium or substrate bound basic fibroblast growth factor (bFGF). Nerve growth factor (NGF) is not a survival factor for these neurons in vitro, but when used in combination with substrate bound bFGF, NGF does vigorously stimulate a neuritogenesis response by these neurons. Transforming growth factor beta (TGF beta 1) enhances the survival effect that bFGF has on these adult auditory neurons but does not by itself promote their survival in dissociated acoustic ganglion cultures. We propose that there may be complex interactions and synergy exerted by these growth factors (i.e. bFGF, NGF, TGF beta 1) during injury to the inner ear.

Peripheral and central target-derived trophic factor(s) effects on auditory neurons.

In the developing inner ear, a naturally occurring programmed cell death of cochleovestibular ganglion (CVG) neurons as well as peripheral and central target-derived trophic effects on survival of embryonic CVG neurons are known. To further analyze these target derived trophic interactions, spiral ganglion explants obtained from 5 day postpartum (P5) rat pups were cultured with an intact organ of Corti and in the absence of Cortis organ. Both neuronal survival and neurite extension were influenced by the presence of this peripheral target tissue. Local destruction of Cortis organ caused both neuritic retraction and neuronal cell death to occur in a corresponding portion of the spiral ganglion. This peripheral target-derived neurotrophic effect may be mediated by a diffusible factor(s) since organ of Corti conditioned medium also had a neurotrophic effect on the survival of auditory neurons in cell cultures of dissociated spiral ganglia from P5 rat pups. A component of central target tissue, i.e. astrocytes, was also shown to release a diffusible factor(s) that supported the survival of dissociated P5 rat spiral ganglion neurons. The neurotrophic effects on the in vitro survival of spiral ganglion neurons by both of these conditioned medium factors were concentration dependent.

Tgf-beta1 Modulates bFGF Receptor Message Expression in Cultured Adult Auditory Neurons

Basic fibroblast growth factor (bFGF) has been shown to have neuronotrophic effects on cultured neurons. Transforming growth factor beta (TGFss1) has been implicated in the modulation of cellular receptors for bFGF in several cell types. In this study, we show that TGFss1 is expressed in cultured adult mouse auditory neurons in response to explanation injury and acts in an autocrine fashion to increase the level of expression of bFGF receptors message in these same neurons. Based on these in-vitro results, we propose that these trophic factors (i.e. TGFss1 and bFGF) play a significant role in the response to injury by the mature auditory system.

Kainate and NMDA toxicity for cultured developing and adult rat spiral ganglion neurons: further evidence for a glutamatergic excitatory neurotransmission at the inner hair cell synapse

In the inner ear, the excitatory amino acid glutamate is a proposed neurotransmitter acting at the synapse between hair cells and afferent auditory neurons. Using cultures of 5-day-old rat auditory neurons, we show that the afferent auditory neuronal population can be divided, on the basis of its sensitivity to the neuronotoxic effect of glutamate and its analogs, in at least 3 subpopulations, one responding to N-methyl-D-aspartate (NMDA), one responding to kainate and a third minor one unresponsive to NMDA, kainic acid and glutamate. No toxic effect of quisqualate is observed. The use of specific antagonists (kynurenate and 2-amino-5-phosphonovalerate (DAP-5) demonstrates the specificity of the receptors to the excitatory amino acids on the afferent auditory neurons. Afferent auditory neurons from adult rats can also be cultured and in these preparations only the large neurons are sensitive to glutamate, kainate and NMDA while the small neurons are not responsive, suggesting that a glutamatergic neurotransmission occurs only at this synapse between the inner hair cells and the large radial afferent auditory neurons. We also show that, in vitro, the organ of Corti releases, in response to an increased potassium concentration and in the presence of calcium, a toxic activity for the afferent auditory neurons that is antagonized by kynurenate and DAP-5. Pathophysiological implications are discussed.

Tgf Beta 1 Expression Is Initiated in Adult Auditory Neurons by Sectioning of the Auditory Nerve

Neuronotrophic factors (e.g. basic fibroblast growth factor, bFGF and nerve growth factor, NGF) have been demonstrated to respectively promote survival and neuritogenesis in cultures of dissociated adult rat spiral ganglia. Transforming growth factor beta (TGF beta 1) has been shown to modulate the response of cultured auditory neurons to bFGF through the induction of high affinity receptors for bFGF in the neurons. In this study, we show that TGF beta is expressed in situ by adult auditory neurons in response to traumatic injury (i.e. transection of the eighth cranial nerve). Based on these in vivo results and on the results from our previous in vitro studies, we propose that TFG beta 1 acts as an early autocrine signal involved in the response to injury by neurons of the peripheral auditor system.

Potassium-induced release of an endogenous toxic activity for outer hair cells and auditory neurons in the cochlea: A new pathophysiological mechanism in Meniere's disease?

In Menières disease, the increase of extracellular potassium concentration in the perilymph is thought to play a key role in determining the progressive loss of cochlear hair cells. In this paper, we describe a serum-free culture preparation of hair cells from 5 day-old rat and report the release by the cochlea, in response to an increase of extracellular potassium concentration, of a cytotoxic activity active on hair cells and auditory neurons. The toxic activity is associated with low molecular weight (less than 10,000 Dalton) molecule(s) as revealed by ultrafiltration. Morphological studies performed on the organ of Corti incubated during 24 h in the presence of the cochlea-derived toxic activity (CTA), show that this factor is toxic for hair cells and not for supporting or surrounding cells. The release of CTA occurs both in the spiral ganglion and in the organ of Corti. We suggest that this cochlea-derived toxic activity may play an important role in the pathophysiology of the hearing loss that occurs during the progression of Menières disease.

Cytokine modulation of basophil histamine release in wasp‐venom allergy

We report the effect of interleukin‐3 (IL‐3) and of other cytokines on antigen‐induced basophil histamine release in wasp‐venom‐allergic subjects. Leukocytes from 12 patients with documented anaphylactic sensitivity to wasp venom were preincubated in the presence or absence of IL‐3, granulocyte/macrophage‐colony stimulating factor (GM‐CSF), IL‐5, IL‐8, or stem cell factor (SCF). Washed cells were then exposed to venom and to other secretagogues, and histamine release in the supernatant was measured fluorometrically. Preincubation of leukocytes with IL‐3, GM‐CSF, or IL‐5 (0.02–2 ng/ml), but not with IL‐8 and SCF, caused a dose‐dependent enhancement of antigen‐induced basophilic histamine release in all subjects tested. Mean maximum increase was about 100% for IL‐3, IL‐5, and GM‐CSF. The priming effect of IL‐3 was rapid, persisted up to 12 h, and was not accompanied by a change in cellular histamine. IL‐3 had a comparable enhancing effect when basophils were triggered with anti‐IgE or N‐formylmethionylphenylalanine (FMP). By contrast, IL‐3 had no effect on substance‐P‐induced histamine release. The significant enhancement of basophil releasability to antigen in wasp‐venom allergy by very low concentrations of IL‐3, GM‐CSF, and IL‐5 suggests that cytokines in the basophil (mast‐cell?) microenvironment could be critical factors in determining the variability of sting reactions in Hymenoptera‐venom‐allergic subjects.

Gastrin levels in serum and bronchoalveolar lavage fluid of patients with lung cancer: comparison with patients with chronic obstructive pulmonary disease.

BACKGROUND: The gastrin gene is known to be expressed in all classes of bronchogenic carcinomas. Furthermore, high levels of gastrin have been reported in both the bronchoalveolar lavage (BAL) fluid and serum of patients with lung cancer. Based on these preliminary data a study was conducted to evaluate the usefulness of gastrin measurements in the diagnosis and staging of lung cancer. METHODS: Thirty-five patients with lung cancer (26 non-small cell (NSCLC) and nine small cell (SCLC)) and 25 patients with chronic obstructive pulmonary disease underwent fibreoptic bronchoscopy and BAL. Gastrin levels were determined in both BAL fluid and the serum and compared with each other and with staging. RESULTS: No difference was found between the gastrin levels in the BAL fluid or serum of the study groups. There was no correlation with the stage in NSCLC and no correlation was found between the gastrin levels in the serum and the BAL fluid. A significant difference was seen in gastrin levels in BAL fluid between extensive and limited SCLC (p < 0.05). CONCLUSION: There is no evidence of clinical usefulness for gastrin measurements in lung cancer.