Acute toxicities and cumulative dose to the brain of repeated sessions of stereotactic radiotherapy (SRT) for brain metastases: a retrospective study of 184 patients.

BACKGROUND: Stereotactic radiation therapy (SRT) is a focal treatment for brain metastases (BMs); thus, 20 to 40% of patients will require salvage treatment after an initial SRT session, either because of local or distant failure. SRT is not exempt from acute toxicity, and the acute toxicities of repeated SRT are not well known. The objective of this study was to analyze the acute toxicities of repeated courses of SRT and to determine whether repeated SRT could lead to cumulative brain doses equivalent to those of whole-brain radiotherapy (WBRT). MATERIAL AND METHODS: Between 2010 and 2020, data from 184 patients treated for 915 BMs via two to six SRT sessions for local or distant BM recurrence without previous or intercurrent WBRT were retrospectively reviewed. Patients were seen via consultations during SRT, and the delivered dose, the use of corticosteroid therapy and neurological symptoms were recorded and rated according to the CTCAEv4. The dosimetric characteristics of 79% of BMs were collected, and summation plans of 76.6% of BMs were created. RESULTS: 36% of patients developed acute toxicity during at least one session. No grade three or four toxicity was registered, and grade one or two cephalalgy was the most frequently reported symptom. There was no significant difference in the occurrence of acute toxicity between consecutive SRT sessions. In the multivariate analysis, acute toxicity was associated with the use of corticosteroid therapy before irradiation (OR = 2.6; p = 0.01), BMV grade (high vs. low grade OR = 5.17; p = 0.02), and number of SRT sessions (3 SRT vs. 2 SRT: OR = 2.64; p = 0.01). The median volume equivalent to the WBRT dose (VWBRT) was 47.9 ml. In the multivariate analysis, the VWBRT was significantly associated with the total GTV (p < 0.001) and number of BMs (p < 0.001). Even for patients treated for more than ten cumulated BMs, the median BED to the brain was very low compared to the dose delivered during WBRT. CONCLUSION: Repeated SRT for local or distant recurrent BM is well tolerated, without grade three or four toxicity, and does not cause more acute neurological toxicity with repeated SRT sessions. Moreover, even for patients treated for more than ten BMs, the VWBRT is low.

Changes in the characteristics of patients treated for brain metastases with repeat stereotactic radiotherapy (SRT): a retrospective study of 184 patients.

PURPOSE: Brain metastases (BMs) are the leading cause of intracranial malignant neoplasms in adults. WHO, Karnofsky performance status (KPS), age, number of BMs, extracerebral progression (ECP), recursive partitioning analysis (RPA), diagnosis-specific graded prognostic assessment (Ds-GPA) are validated prognostic tools to help clinicians decide on treatment. No consensus exists for repeat stereotactic radiotherapy (SRT) for BMs. The aim of this study was to review the changes in patient characteristics treated with repeated SRTs. METHODS AND MATERIALS: The data of patients treated between 2010 and 2020 with at least two courses of SRT without previous whole brain radiotherapy (WBRT) were reviewed. Age, WHO, KPS, ECP, type of systemic treatment, number of BMs were recorded. RPA, Ds-GPA and brain metastasis velocity (BMV) were calculated. RESULTS: 184 patients were treated for 915 BMs and received two to six SRTs for local or distant brain recurrence. The median number of BMs treated per SRT was 1 (range: 1-6), for a median of 4 BMs treated during all sessions (range: 2-19). WHO, Ds-GPA and RPA were stable between each session of SRT, whereas KPS was significantly better in SRT1 than in the following SRT. The number of BMs was not significantly different between each SRT, but there was a tendency for more BM at SRT1 (p = 0.06). At SRT1, patients had largest BM and undergo more surgery than during the following SRT (p < 0.001). 6.5%, 37.5% and 56% of patients were classified as high, intermediate, and low BMV, respectively, at the last SRT session. There was almost perfect concordance between the BMV-grade calculated at the last SRT session and at SRT2 (r = 0.89; p < 0.001). CONCLUSION: Repeated SRT doesn't lead to a marked alteration in the general condition, KPS was maintained at over 70% for more than 95% of patients during all SRTs. Long survival can be expected, especially in low-grade BMV patients. WBRT shouldn't be aborted, especially for patients developing more than twelve BMs annually.

Guidelines of the French Society of ENT (SFORL): Drug-induced sleep endoscopy in adult obstructive sleep apnea syndrome.

OBJECTIVES: To determine the indications, anesthesiological and surgical procedure and interest of drug-induced sleep endoscopy in the treatment of adult obstructive sleep apnea syndrome. DESIGN: A redactional committee of 17 experts was set up. Conflicts of interest were disclosed and followed up throughout the process of drawing up the guidelines. The work received no funding from any firm dealing in health products (drugs or devices). The GRADE (Grading of Recommendations Assessment, Development and Evaluation) method was applied to assess the quality of the data on which the guidelines were founded. It was stressed that strong recommendations should not be made on the basis of poor-quality or insufficient data. METHODS: The committee studied 29 questions on 5 topics: indications and contraindications, anesthetic technique, surgical technique, interpretation and reporting of results, and management guided by results. RESULTS: Expert review and application of the GRADE method led to 30 guidelines: 10 with high level of evidence (Grade 1+ or 1-), 19 with low level (GRADE 2+ or 2-) and 1 expert opinion. CONCLUSION: Experts fully agreed on the strong guidelines formalizing the indications and modalities of drug-induced sleep endoscopy for adult obstructive sleep apnea syndrome.

[Skull base meningioma: Clinical and radiological efficacy based on a quantitative volumetric analysis]. / Méningiomes de la base du crâne : efficacité clinique et radiologique basée sur une analyse volumétrique quantitative.

PURPOSE: To date, no correlation has been found between clinical and radiological efficacy after irradiation of skull base meningiomas. However, the evaluation of the radiological response was most often made by questionable methods that may have underestimated the radiological effectiveness of radiotherapy. The objective of this work is to verify this hypothesis by quantitative volumetric analysis. MATERIAL AND METHODS: Data from 35 patients treated with either helical tomotherapy (45.7%) or fractionated stereotactic radiotherapy (54.3%) were retrospectively analysed. These were mainly women (94%) aged 59 (43-81) with lesions mainly of the cavernous sinus (60%). There was a median of 2 (1-4) symptoms and the main symptoms were visual impairment (39%), cranial nerve deficits (23.4%) and headaches (17.2%). RESULTS: Median tumour volume decreased significantly (P<0.05) from 9.6mL (0.3-36.6) to 6.8mL (0.1-26.5) after median follow-up of 44 months (24-77). Sixty-three percent of patients had an improvement of at least one symptom. In univariate analysis, clinical efficacy (P<0.05), radiotherapy technique (P<0.05), tumor topography (P<0.05) and initial tumor volume (P<0.05) were predictive factors for radiological response. In multivariate analysis, only the inverse correlation between radiological response and initial tumor volume remained significant (ρ: -0.47 95% CI -3.2 to 5.7; P<0.05). CONCLUSION: The quantitative volumetric monitoring demonstrates a major radiological efficiency of radiotherapy. However, no clear correlation between clinical and radiological efficacy was found.

[Cost of radiotherapy for bone metastases in France: A monocentric retrospective study]. / Coût de la radiothérapie des métastases osseuses en France : étude rétrospective monocentrique.

PURPOSE: The cost of radiotherapy is a concern for health systems. The conventional non fractionated or multifractionated schemes have shown the same efficacy in terms of pain relief but a non fractionated treatment seems less expensive. However, in general practice, multifractionated treatments are still the majority, which represents an additional cost for society. Moreover, the use of stereotactic body radiotherapy becomes more democratic and offers new curative perspectives, but at what price? MATERIAL AND METHODS: A monocentric retrospective study was conducted in a French radiotherapy department to evaluate and compare the cost of irradiation of uncomplicated bone metastases according to the selected radiotherapy regimen : 30Gy in 10 fractions, 20Gy in five fractions, 8Gy in one fraction or stereotactic body radiotherapy. RESULTS: Between January 2014 and December 2015, 91 patients receiving 116 treatments were included in the study, including 44 men (48%) and 47 women (52%) were 63 years old (25-88 years). Thirty-four treatments (29%) were performed by 30Gy in 10 fractions (30Gy group), 24 treatments (21%) by 20Gy in 5 fractions (20Gy group), 25 treatments (22%) by 8Gy in one fraction (8Gy group) and 33 treatments (28%) by stereotactic body radiotherapy (SBRT group). The cost of stereotactic body radiotherapy was significantly higher than that of three-dimensional treatments (P<0.001). If the cost of transport was added to this cost, stereotactic body radiotherapy remained the most expensive (P<0.001). The cost of the irradiation delivering 30Gy treatment was significantly higher than the cost of treatment with 20Gy (P=0.006) or 8Gy (P<0.001), even after adding the transport cost (P<0.001), with no significant difference between 20Gy and 8Gy (P=0.11). For the overall cost of treatment including the total cost of treatments, associated transport and reirradiation, stereotactic body radiotherapy was the most expensive treatment (P<0.001) and this cost was significantly higher in the 30Gy group than in the 20Gy group (P=0.012) or 8Gy group (P=0.001), with no significant difference between 20Gy and 8Gy (P=0.38). There was no significant difference in the cost of follow-up between 30Gy, 20Gy, 8Gy and stereotactic body radiotherapy at one month (P=0.09) but at three months (P=0.01) and six months (P=0.0001), this cost was significantly higher after a three-dimensional treatment. There was no significant difference in overall cost including initial radiotherapy, transport and overall follow-up over 6 months between groups (P=0.04). CONCLUSION: Stereotactic body radiotherapy is an efficient and curative irradiation technique but more expensive. It is preferred for some patients with a longer life expectancy in a non-palliative treatment setting. The treatment delivering 8Gy treatment appears to be the most cost-effective while leading to an equivalent efficiency to multifractionated treatments and preserving the quality of life of patients.

[Bone metastases radiotherapy: Multi-approaches literature review]. / Radiothérapie des métastases osseuses : revue multi-approches de la littérature.

External beam radiation therapy is an efficient treatment, which relieves pain associated with bone metastases, and is prescribed in worldwide. Although bone metastases palliative irradiation recommendations exist, international clinical practices remain variable. The purpose of this article is to show the clinical practices evolution though clinical trials, cost studies and techniques' progression.

[Radiotherapy of bone metastases in France: A descriptive monocentric retrospective study]. / Radiothérapie des métastases osseuses en France : étude descriptive rétrospective monocentrique.

PURPOSE: Bone metastases cause pain and affect patients' quality of life. Radiation therapy is one of the reference analgesic treatments. The objective of this study was to compare the current practices of a French radiotherapy department for the treatment of uncomplicated bone metastases with data from the literature in order to improve and optimize the management of patients. MATERIAL AND METHODS: A retrospective monocentric study of patients who underwent palliative irradiation of uncomplicated bone metastases was performed. RESULTS: Ninety-one patients had 116 treatments of uncomplicated bone metastases between January 2014 and December 2015, including 44 men (48%) and 47 women (52%) with an average age of 63years (25-88years). Primary tumours most commonly found were breast cancer (35%), lung cancer (16%) and prostate cancer (12%). The regimens used were in 29% of cases 30Gy in ten fractions (group 30Gy), in 21% of cases 20Gy in five fractions (group 20Gy), in 22% of cases 8Gy in one fraction (group 8Gy) and in 28% of cases 23.31Gy in three fractions of stereotactic body irradiation (stereotactic group). The general condition of the patient (P<0.001), pain score and analgesic (P<0.001), oligometastatic profile (P=0.003) and practitioner experience (P<0.001) were factors influencing the choice of the regimen irradiation. Age (P=0.46), sex (P=0.14), anticancer treatments (P=0.56), concomitant hospitalization (P=0.14) and the distance between the radiotherapy centre and home (P=0.87) did not influence the decision significantly. A total of three cases of spinal compression and one case of post-therapeutic fracture were observed, occurring between one and 128days and 577days after irradiation, respectively. Eight percent of all irradiated metastases were reirradiated with a delay ranging between 13 and 434days after the first irradiation. The re-irradiation rate was significantly higher after 8Gy (P=0.02). The rate of death was significantly lower in the stereotactic arm (P<0.001) and overall survival was significantly greater in the stereotactic arm (P<0.001). CONCLUSION: This study showed that patients' analysed was comparable to the population of different studies. Predictive factors for the choice of the treatment regimen were identified. Non-fractionnated therapy was underutilised while stereotactic treatment was increasingly prescribed, showing an evolution in the management of patients.

An in vitro study of the sub-cellular distribution of nicotinic receptors.

Nicotinic and serotoninergic 5HT3 receptors share important sequence identities except for their cytoplasmic loop. Both ends of this loop display conserved 3D helical structures with distinct primary sequences. We decided to check whether these two helices named F and G play a role in the sub-cellular distribution of different nicotinic receptors. We systematically exchanged each helix with the equivalent sequence of neuronal nicotinic and alpha4, beta2 and alpha7 subunits in the functional chimeric alpha7-5HT3 receptor used as a model system. The new chimeras were expressed in vitro in polarized epithelial cells from pig kidney. We quantified synthesis and export of the receptors to the cell surface by measuring alpha-bungarotoxin binding sites. Immunogold labelling was used, at the electron microscope level, to determine the amount of each chimera present at either domain, apical and/or basolateral, of these cells. We noticed that in epithelial cells the majority of alpha-bungarotoxin binding sites remained sequestered in the cytoplasm as already observed in neurons in vivo. The majority of the pentamers present at the cell surface were located at the apical domain. Our results suggest that helix F and G differently regulate assembly and export to the cell surface of alpha-bungarotoxin binding receptors.

Chimaeric nicotinic-serotonergic receptor combines distinct ligand binding and channel specificities.

The neuronal nicotinic alpha 7 (nAChR) and 5-hydroxytryptamine (5HT3) receptors are ligand-gated ion channels with a homologous topological organization and have activation and desensitization reactions in common. Yet these homo-oligomeric receptors differ in the pharmacology of their binding sites for agonists and competitive antagonists, and in their sensitivity to Ca2+ ions. The alpha 7 channel is highly permeable to Ca2+ ions and external Ca2+ ions potentiate, in an allosteric manner, the permeability response to acetylcholine, as shown for other neuronal nAChRs. The 5HT3 channel, in contrast, is not permeable to Ca2+ ions, but blocked by them. To assign these properties to delimited domains of the primary structure, we constructed several recombinant chimaeric alpha 7-5HT3 receptors. We report here that one of the constructs expresses a functional receptor that contains the serotonergic channel still blocked by Ca2+ ions, but is activated by nicotinic ligands and potentiated by external Ca2+ ions.

Negative regulatory elements upstream of a novel exon of the neuronal nicotinic acetylcholine receptor alpha 2 subunit gene.

The expression of the nicotinic acetylcholine receptor alpha 2 subunit gene is highly restricted to the Spiriform lateralis nucleus of the Chick diencephalon. As a first step toward understanding the molecular mechanism underlying this regulation, we have investigated the structural and regulatory properties of the 5' sequence of this gene. A strategy based on the ligation of an oligonucleotide to the first strand of the cDNA (SLIC) followed by PCR amplification was used. A new exon was found approximately 3kb upstream from the first coding exon, and multiple transcription start sites of the gene were mapped. Analysis of the flanking region shows many consensus sequences for the binding of nuclear proteins, suggesting that the 1 kb flanking region contains at least a portion of the promoter of the gene. We have analysed the negative regulatory elements present within this region and found that a silencer region located between nucleotide -144 and +76 is active in fibroblasts as well as in neurons. This silencer is composed of six tandem repeat Oct-like motifs (CCCCATGCAAT), but does not bind any member of the Oct family. Moreover these motifs were found to act as a silencer only when they were tandemly repeated. When two, four or five motifs were deleted, the silencer activity of the motifs unexpectedly became an enhancer activity in all cells we have tested.

Functional significance of aromatic amino acids from three peptide loops of the alpha 7 neuronal nicotinic receptor site investigated by site-directed mutagenesis.

Three aromatic amino acids, Tyr92, Trp148 and Tyr187 belonging to three separate domains of the alpha 7-subunit of neuronal nicotinic acetylcholine receptor were mutated to phenylalanine, and the electrophysiological response of the resulting mutant receptors analyzed in the Xenopus oocyte expression system. All mutations significantly decreased the apparent affinities for acetylcholine and nicotine, and to a lesser extent, those for the competitive antagonists dihydro-beta-erythroidine and alpha-bungarotoxin. Other properties investigated, such as the voltage dependency of the ion response as well as its sensitivity to the open channel blocker QX222, were not significantly changed, indicating that the mutations affected selectively the recognition of cholinergic ligands by the receptor protein. The maximal rates for the rapid desensitization process were slightly modified, suggesting that the contribution of Tyr92, Trp148 and Tyr187 to the binding area might differ in the various conformations of the nicotinic receptor. Other mutations at nearby positions (S94N, W153F, G151D and G82E) did not affect the properties of the electrophysiological response. These data point to the functional significance of Tyr92, Trp148 and Tyr187 in the binding of cholinergic ligands and ion channel activation of the nicotinic receptor, thus supporting a multiple loop model [(1990) J. Biol. Chem. 265, 10430-10437] for the ligand binding area.

Asynchronous assembly of the acetylcholine receptor and of the 43-kD nu1 protein in the postsynaptic membrane of developing Torpedo marmorata electrocyte.

The assembly of the nicotinic acetylcholine receptor (AchR) and the 43-kD protein (v1), the two major components of the post synaptic membrane of the electromotor synapse, was followed in Torpedo marmorata electrocyte during embryonic development by immunocytochemical methods. At the first developmental stage investigated (45-mm embryos), accumulation of AchR at the ventral pole of the newly formed electrocyte was observed within columns before innervation could be detected. No concomitant accumulation of 43-kD immunoreactivity in AchR-rich membrane domains was observed at this stage, but a transient asymmetric distribution of the extracellular protein, laminin, which paralleled that of the AchR, was noticed. At the subsequent stage studied (80-mm embryos), codistribution of the two proteins was noticed on the ventral face of the cell. Intracellular pools of AchR and 43-kD protein were followed at the EM level in 80-mm electrocytes. AchR immunoreactivity was detected within membrane compartments, which include the perinuclear cisternae of the endoplasmic reticulum and the plasma membrane. On the other hand, 43-kD immunoreactivity was not found associated with the AchR in the intracellular compartments of the cell, but codistributed with the AchR at the level of the plasma membrane. The data reported in this study suggest that AchR clustering in vivo is not initially determined by the association of the AchR with the 43-kD protein, but rather relies on AchR interaction with extracellular components, for instance from the basement membrane, laid down in the tissue before the entry of the electromotor nerve endings.

Complete mRNA coding sequence of the acetylcholine binding alpha-subunit of Torpedo marmorata acetylcholine receptor: a model for the transmembrane organization of the polypeptide chain.

A 1,350-base-pair-long cDNA clone, named p alpha-2, was isolated by hybridization to the previously characterized clone p alpha-1 and found to be specific for the alpha-subunit of the Torpedo marmorata acetylcholine receptor. The nucleotide sequences of both cDNA inserts were analyzed and the sequence of the complete coding region and part of the 5' and 3' untranslated regions of the alpha-chain mRNA was determined. The complete amino acid sequence of the alpha-chain precursor is presented and used to develop a model for the transmembrane organization of the polypeptide.

Identification of a cDNA clone coding for the acetylcholine binding subunit of Torpedo marmorata acetylcholine receptor.

A recombinant DNA plasmid has been constructed that contains sequences of the gene coding for the acetylcholine binding subunit (alpha-subunit, 40 000 daltons) of Torpedo marmorata acetylcholine receptor protein (AChR). Polyadenylated RNA purified from Torpedo electric organ was used to construct a cDNA library. The AChR alpha-subunit cDNA clone was then identified by a two-step screening of 700 recombinant clones. As AChR is present in Torpedo electric organ but not in Torpedo liver or spleen, differential screening led to the selection of 12 clones specific for the electric organ. We then tested the ability of cDNA inserts to hybridize alpha-subunit mRNA specifically, as judged by cell-free translation and immunoprecipitation. The insert from one clone, p alpha-1, selectively hybridized with a mRNA species which elicited the synthesis of a 38 000 mol. wt. polypeptide. This polypeptide was precipitated by: (1) a rabbit serum raised against purified denatured alpha-subunit (the pure alpha-subunit displaced the complex); and (2) a rat monoclonal antibody specific for the denatured alpha-subunit. It was thus identified as a precursor of the alpha chain. Blot hybridization analysis of polyadenylated RNA from Torpedo electric organ with the p alpha-1 probe revealed a major species of 2.0 kb, which thus contains approximately 800 non-coding nucleotides.