Available evidence on re-irradiation with stereotactic ablative radiotherapy following high-dose previous thoracic radiotherapy for lung malignancies.

Patients affected with intra-thoracic recurrences of primary or secondary lung malignancies after a first course of definitive radiotherapy have limited therapeutic options, and they are often treated with a palliative intent. Re-irradiation with stereotactic ablative radiotherapy (SABR) represents an appealing approach, due to the optimized dose distribution that allows for high-dose delivery with better sparing of organs at risk. This strategy has the goal of long-term control and even cure. Aim of this review is to report and discuss published data on re-irradiation with SABR in terms of efficacy and toxicity. Results indicate that thoracic re-irradiation may offer satisfactory disease control, however the data on outcome and toxicity are derived from low quality retrospective studies, and results should be cautiously interpreted. As SABR may be associated with serious toxicity, attention should be paid for an accurate patients' selection.

Transcriptional regulator PRDM12 is essential for human pain perception.

Pain perception has evolved as a warning mechanism to alert organisms to tissue damage and dangerous environments. In humans, however, undesirable, excessive or chronic pain is a common and major societal burden for which available medical treatments are currently suboptimal. New therapeutic options have recently been derived from studies of individuals with congenital insensitivity to pain (CIP). Here we identified 10 different homozygous mutations in PRDM12 (encoding PRDI-BF1 and RIZ homology domain-containing protein 12) in subjects with CIP from 11 families. Prdm proteins are a family of epigenetic regulators that control neural specification and neurogenesis. We determined that Prdm12 is expressed in nociceptors and their progenitors and participates in the development of sensory neurons in Xenopus embryos. Moreover, CIP-associated mutants abrogate the histone-modifying potential associated with wild-type Prdm12. Prdm12 emerges as a key factor in the orchestration of sensory neurogenesis and may hold promise as a target for new pain therapeutics.

Infectiologie et postulats de Koch: tourner la page [Infectious diseases and Koch's postulates: turning the page].

The thoracolumbar junctional region (T10-L1) of the spine is a transitional zone, where more than half of the thoracic and lumbar fractures occur. In this presentation the origin of the pathoanatomical changes in the thoracolumbar junctional region of the spine is discussed in view of the previous studies. These studies refer to a torsional force contributing to the formation of the degenerative changes, especially in the facet joints. Degenerative changes anteriorly and posteriorly do not concur in the thoracolumbar junctional region. Only a weak concurrence is found between disc degeneration and spondylosis, which refer to differences in their pathomechanisms. A strong concurrence between the degenerative changes at different levels, especially anteriorly, reflects factors causing overall degeneration in the thoracolumbar junctional region.

Energetics and mechanics of walking in patients with chronic low back pain and healthy matched controls.

PURPOSE: Walking in patients with chronic low back pain (cLBP) is characterized by motor control adaptations as a protective strategy against further injury or pain. The purpose of this study was to compare the preferred walking speed, the biomechanical and the energetic parameters of walking at different speeds between patients with cLBP and healthy men individually matched for age, body mass and height. METHODS: Energy cost of walking was assessed with a breath-by-breath gas analyser; mechanical and spatiotemporal parameters of walking were computed using two inertial sensors equipped with a triaxial accelerometer and gyroscope and compared in 13 men with cLBP and 13 control men (CTR) during treadmill walking at standard (0.83, 1.11, 1.38, 1.67 m s(-1)) and preferred (PWS) speeds. Low back pain intensity (visual analogue scale, cLBP only) and perceived exertion (Borg scale) were assessed at each walking speed. RESULTS: PWS was slower in cLBP [1.17 (SD = 0.13) m s(-1)] than in CTR group [1.33 (SD = 0.11) m s(-1); P = 0.002]. No significant difference was observed between groups in mechanical work (P ≥ 0.44), spatiotemporal parameters (P ≥ 0.16) and energy cost of walking (P ≥ 0.36). At the end of the treadmill protocol, perceived exertion was significantly higher in cLBP [11.7 (SD = 2.4)] than in CTR group [9.9 (SD = 1.1); P = 0.01]. Pain intensity did not significantly increase over time (P = 0.21). CONCLUSIONS: These results do not support the hypothesis of a less efficient walking pattern in patients with cLBP and imply that high walking speeds are well tolerated by patients with moderately disabling cLBP.

Dendritic Spine Abnormalities in Hippocampal CA1 Pyramidal Neurons Underlying Memory Deficits in the SAMP8 Mouse Model of Alzheimer's Disease

SAMP8 is a strain of mice with accelerated senescence. These mice have recently been the focus of attention as they show several alterations that have also been described in Alzheimer"s disease (AD) patients. The number of dendritic spines, spine plasticity, and morphology are basic to memory formation. In AD, the density of dendritic spines is severely decreased. We studied memory alterations using the object recognition test. We measured levels of synaptophysin as a marker of neurotransmission and used Golgi staining to quantify and characterize the number and morphology of dendritic spines in SAMP8 mice and in SAMR1 as control animals. While there were no memory differences at 3 months of age, the memory of both 6- and 9-month-old SAMP8 mice was impaired in comparison with age-matched SAMR1 mice or young SAMP8 mice. In addition, synaptophysin levels were not altered in young SAMP8 animals, but SAMP8 aged 6 and 9 months had less synaptophysin than SAMR1 controls and also less than 3-month-old SAMP8 mice. Moreover, while spine density remained stable with age in SAMR1 mice, the number of spines started to decrease in SAMP8 animals at 6 months, only to get worse at 9 months. Our results show that from 6 months onwards SAMP8 mice show impaired memory. This age coincides with that at which the levels of synaptophysin and spine density decrease. Thus, we conclude that together with other studies that describe several alterations at similar ages, SAMP8 mice are a very suitable model for studying AD.

The effect on lower spine muscle activation of walking on a narrow beam in virtual reality

To what extent do people behave in immersive virtual environments as they would in similar situations in a physical environment? There are many ways to address this question, ranging from questionnaires, behavioral studies, and the use of physiological measures. Here, we compare the onsets of muscle activity using surface electromyography (EMG) while participants were walking under three different conditions: on a normal floor surface, on a narrow ribbon along the floor, and on a narrow platform raised off the floor. The same situation was rendered in an immersive virtual environment (IVE) Cave-like system, and 12 participants did the three types of walking in a counter-balanced within-groups design. The mean number of EMG activity onsets per unit time followed the same pattern in the virtual environment as in the physical environment-significantly higher for walking on the platform compared to walking on the floor. Even though participants knew that they were in fact really walking at floor level in the virtual environment condition, the visual illusion of walking on a raised platform was sufficient to influence their behavior in a measurable way. This opens up the door for this technique to be used in gait and posture related scenarios including rehabilitation.

Relationship between sedimentation sign and morphological grade in symptomatic lumbar spinal stenosis.

PURPOSE: We aimed to study the relationship between two morphological parameters recently described on MRI images in relation to lumbar spinal stenosis (LSS): the first is the sedimentation sign (SedS) and the second is the morphological grading of lumbar stenosis. MATERIALS AND METHODS: MRIs from a total of 137 patients were studied. From those, 110 were issued from a prospective database of symptomatic LSS patients, of whom 73 were treated surgically and 37 conservatively based on symptom severity. A third group consisting of 27 subjects complaining of low back pain (LBP) served as control. Severity of stenosis was judged at disc level using the four A to D grade morphological classification. The presence of a SedS was judged at pedicle level, above or below the site of maximal stenosis. RESULTS: A positive SedS was observed in 58, 69 and 76 % of patients demonstrating B, C and D morphology, respectively, but in none with grade A morphology. The SedS was positive in 67 and 35 % of the surgically and conservatively treated patients, respectively, and in 8 % of the LBP group. C and D morphological grades were present in 97 and 35 % of patients in the surgically and conservatively treated group, respectively, and in 18 % of the LBP group. Presence of a positive SedS carried an increased risk of being submitted to surgery in the symptomatic LSS group (OR 3.5). This risk was even higher in the LSS patients demonstrating grade C or D morphology (OR 65). DISCUSSION AND CONCLUSION: One-third of surgically treated LSS patients do not present a SedS. This sign appears to be a lesser predictor of treatment modality in our setting of symptomatic LSS patients compared to the severity of stenosis judged by the morphological grade.

EEG reactivity to pain in comatose patients: Importance of the stimulus type.

INTRODUCTION: Electroencephalogram (EEG) background reactivity is a potentially interesting outcome predictor in comatose patients, especially after cardiac arrest, but recent studies report only fair interrater reliability. Furthermore, there are no definite guidelines for its testing. We therefore investigated the EEG effect of standardized noxious stimuli in comatose patients not reactive to auditory stimuli. METHODS: In this prospective study we applied a protocol using three different painful stimuli (bilateral nipple pinching, pinprick at the nose base, finger-nail compression on each side), grouped in three distinct clusters with an alternated sequence, during EEG recordings in comatose patients. We only analyzed recordings showing any reactivity to pain. Fisher and χ2 tests were used as needed to assess contingency tables. RESULTS: Of 42 studies, 12 did not show any background reactivity, 2 presented SIRPIDs, and 2 had massive artefacts; we thus analyzed 26 EEGs recorded in 17 patients (4 women, 24%). Nipple pinching more frequently induced a change in EEG background activity (p<0.001), with a sensitivity of 97.4% for reactivity. Neither the order of the stimuli in the cluster (p=0.723), nor the cluster order (p=0.901) influenced the results. CONCLUSION: In this pilot study, bilateral, synchronous nipple pinching seems to be the most efficient method to test nociceptive EEG reactivity in comatose patients. This approach may enhance interrater reliability, but deserves confirmation in larger cohorts.

Orofacial pain of cardiac origin, serial of clinical cases

Objective: To determine the clinical characteristics of the orofacial pain of cardiac origin in patients visited when doing a treadmill exercise test, at the cardiology service of the Can Ruti Hospital in Badalona (Barcelona, Spain). Study design: The sample of that study included thirty patients visiteding when doing a treadmill exercise test, at the cardiology service. The questionnaire has been asked to a sample of 30 patients. Results: Eleven of the 30 patients included in this study presented craniofacial pain before or during the cardiac seizure. The location of the pain was bilateral, non-irradiated at the mandible in all cases. The intensity of the pain was from slight to severe. The frequency of the appearance of the pain was paroxysmal in 8 cases and constant in three cases, and the duration was from a few hours to a maximum of 14 days. Discussion: The cardiac pain in craniofacial structures is usually bilateral, compared to odontogenic pain which is always unilateral. The pain of cardiac origin is considered atypical because of its location, but about the 10 % of the cases, the cardiac ischemia has its primary manifestation in orofacial structures. Conclusions: Eleven patients referred a bilateral non-irradiated mandibular pain, with intensity from slight to severe, and with a paroxystic frequency in eight cases and a constant frequency in three cases. Just one patient referred pain during the treadmill exercise test. In all cases the pain disappeared after the cardiac surgery or the administration of vasodilators.

Mieux comprendre le syndrome douloureux fémoro-patellaire... pour mieux le traiter [Patellofemoral pain syndrome: understand better in order to treat better].

Le syndrome douloureux fémoro-patellaire (SDFP) est l'une des causes les plus fréquentes de douleur antérieure du genou chez l'adolescent et l'adulte. De par son étiologie complexe, multifactorielle et encore mal comprise, sa prise en charge est un important challenge pour le praticien. Le diagnostic se fait principalement sur l'anamnèse et l'examen clinique du genou mais aussi de l'ensemble du membre inférieur, pouvant parfois nécessiter la réalisation d'une imagerie. Le traitement est dans la grande majorité des cas conservateur, principalement axé sur la rééducation avec de la physiothérapie ciblée et personnalisée. Le traitement chirurgical est réservé aux cas présentant une anomalie structurelle causale. Patellofemoral pain syndrome (PFPS) is one of the most frequent cause of anterior knee pain in adolescents and adults. Due to its complex etiology, which is multifactorial and still poorly understood, its management is a major challenge for the practitioner. The diagnosis is made primarily on the history and clinical examination of the knee, but also of the entire lower limb, which may sometimes require the completion of imaging. The treatment is mostly conservative, focussing on rehabilitation with targeted and personalized therapy. Surgical treatment is reserved for cases with a causal structural lesion.

Traumatisme isolé du thorax chez la personne âgée [Isolated chest trauma in elderly patients].

In elderly patients, a blunt trauma of the chest is associated with a significant risk of complications and mortality. The number of ribs fractures (≥ 4), the presence of bilateral rib fractures, of a pulmonary contusion, of existent comorbidities or acute extra-thoracic traumatic lesions, and lastly the severity of thoracic pain, are indeed important risk factors of complications and mortality. Their presence may require hospitalization of the patient. When complications do occur, they are represented by alveolar hypoventilation, pulmonary atelectasia and broncho-pulmonary infections. When hospitalization is required, it may allow for the specific treatment of thoracic pain, including locoregional anesthesia techniques.

Prevalence and clinical outcomes for patients with MET protein expression in patients with non-small cell lung cancer in Europe: Results from the European Thoracic Oncology Platform Lungscape Project.

Aim The reported prevalence of MET overexpression varies from 25-55% in non-small cell lung cancer (NSCLC) and clinical correlations are emerging slowly. In a well-defined NSCLC cohort of the Lungscape program, we explore the epidemiology, the natural history of IHC MET positivity and its association to OS, RFS and TTR. Methods Resected stage I-III NSCLC identified based on the quality of clinical data and FFPE tissue availability were assessed for MET expression using immunohistochemistry (IHC) on TMAs (CONFIRM anti total c-MET assay, clone SP44, Ventana BenchMark platform). All cases were analysed at participating pathology laboratories using the same protocol, after passing an external quality assurance program. MET positive status is defined as ≥ 50% of tumor cells staining with 2+ or 3+ intensity. Results A total of 2709 cases are included in the iBiobank and will be analysed. IHC MET expression is currently available for 1552 patients, with positive MET IHC staining in 380 cases [24.5%; IHC 3+ in 157 cases (41.3%) and 2+ in 223 cases (58.7%)]. The cohort of 1552 patients includes 48.2%, 44.7% and 4.4% cases of adenocarcinoma, squamous and large cell histologies, respectively. IHC MET status was independent of stage, age and smoking history. Significant differences in MET positivity were associated with gender (32% vs. 21% for female vs. male, p < 0.001), with performance status (25% vs. 18% for 0 vs. 1-3, p = 0.006), and histology (34%, 14% and 24% for adenocarcinoma, squamous and large cell carcinoma, p < 0.001). IHC MET positivity was independent of the IHC ALK status (p = 0.08). At last FU, 52% of patients were still alive, with a median FU of 4.8 yrs. No association of IHC MET was found with OS, RFS or TTR. Conclusions The preliminary results for this large multicentre European cohort describe a prevalence of MET overexpression that seems lower than previous observations in NSCLC, such as reported for the OAM4971g trial, suggesting potential biological differences between surgically resected and metastatic disease. Analysis for the full cohort is ongoing and results will be presented. Disclosure L. Bubendorf: Disclosures: Stock ownership: Roche Advisory boards: Roche, Pfizer Research support: Roche; K. Schulze: Full time employee of Roche; A. Das-Gupta: I am a full time employee of Roche. All other authors have declared no conflicts of interest.

Post-translational modifications of voltage-gated sodium channels in chronic pain syndromes.

In the peripheral sensory nervous system the neuronal expression of voltage-gated sodium channels (Navs) is very important for the transmission of nociceptive information since they give rise to the upstroke of the action potential (AP). Navs are composed of nine different isoforms with distinct biophysical properties. Studying the mutations associated with the increase or absence of pain sensitivity in humans, as well as other expression studies, have highlighted Nav1.7, Nav1.8, and Nav1.9 as being the most important contributors to the control of nociceptive neuronal electrogenesis. Modulating their expression and/or function can impact the shape of the AP and consequently modify nociceptive transmission, a process that is observed in persistent pain conditions. Post-translational modification (PTM) of Navs is a well-known process that modifies their expression and function. In chronic pain syndromes, the release of inflammatory molecules into the direct environment of dorsal root ganglia (DRG) sensory neurons leads to an abnormal activation of enzymes that induce Navs PTM. The addition of small molecules, i.e., peptides, phosphoryl groups, ubiquitin moieties and/or carbohydrates, can modify the function of Navs in two different ways: via direct physical interference with Nav gating, or via the control of Nav trafficking. Both mechanisms have a profound impact on neuronal excitability. In this review we will discuss the role of Protein Kinase A, B, and C, Mitogen Activated Protein Kinases and Ca++/Calmodulin-dependent Kinase II in peripheral chronic pain syndromes. We will also discuss more recent findings that the ubiquitination of Nav1.7 by Nedd4-2 and the effect of methylglyoxal on Nav1.8 are also implicated in the development of experimental neuropathic pain. We will address the potential roles of other PTMs in chronic pain and highlight the need for further investigation of PTMs of Navs in order to develop new pharmacological tools to alleviate pain.