Non-Trigeminal Nociceptive Innervation of the Posterior Dura: Implications to Occipital Headache.

Current understanding of the origin of occipital headache falls short of distinguishing between cause and effect. Most preclinical studies involving trigeminovascular neurons sample neurons that are responsive to stimulation of dural areas in the anterior 2/3 of the cranium and the periorbital skin. Hypothesizing that occipital headache may involve activation of meningeal nociceptors that innervate the posterior ⅓ of the dura, we sought to map the origin and course of meningeal nociceptors that innervate the posterior dura overlying the cerebellum. Using AAV-GFP tracing and single-unit recording techniques in male rats, we found that neurons in C2-C3 DRGs innervate the dura of the posterior fossa; that nearly half originate in DRG neurons containing CGRP and TRPV1; that nerve bundles traverse suboccipital muscles before entering the cranium through bony canals and large foramens; that central neurons receiving nociceptive information from the posterior dura are located in C2-C4 spinal cord and that their cutaneous and muscle receptive fields are found around the ears, occipital skin and neck muscles; and that administration of inflammatory mediators to their dural receptive field, sensitize their responses to stimulation of the posterior dura, peri-occipital skin and neck muscles. These findings lend rationale for the common practice of attempting to alleviate migraine headaches by targeting the greater and lesser occipital nerves with anesthetics. The findings also raise the possibility that such procedures may be more beneficial for alleviating occipital than non-occipital headaches and that occipital migraines may be associated more closely with cerebellar abnormalities than in non-occipital migraines.SIGNIFICANCE STATEMENT Occipital headaches are common in both migraine and non-migraine headaches. Historically, two distinct scenarios have been proposed for such headaches; the first suggests that the headaches are caused by spasm or tension of scalp, shoulders, and neck muscles inserted in the occipital region, whereas the second suggests that these headaches are initiated by activation of meningeal nociceptors. The current study shows that the posterior dura overlying the cerebellum is innervated by cervicovascular neurons in C2 DRG whose axons reach the posterior dura through multiple intracranial and extracranial pathways, and sensitization of central cervicovascular neurons from the posterior dura can result in hyper-responsiveness to stimulation of neck muscles. The findings suggest that the origin of occipital and frontal migraine may differ.

Neural mechanism for hypothalamic-mediated autonomic responses to light during migraine.

Migraineurs avoid light because it intensifies their headache. However, this is not the only reason for their aversion to light. Studying migraineurs and control subjects, we found that lights triggered more changes in autonomic functions and negative emotions during, rather than in the absence of, migraine or in control subjects, and that the association between light and positive emotions was stronger in control subjects than migraineurs. Seeking to define a neuroanatomical substrate for these findings, we showed that, in rats, axons of retinal ganglion cells converge on hypothalamic neurons that project directly to nuclei in the brainstem and spinal cord that regulate parasympathetic and sympathetic functions and contain dopamine, histamine, orexin, melanin-concentrating hormone, oxytocin, and vasopressin. Although the rat studies define frameworks for conceptualizing how light triggers the symptoms described by patients, the human studies suggest that the aversive nature of light is more complex than its association with headache intensification.

Tracking patients with chronic occipital headache after occipital nerve decompression surgery: A case series.

BACKGROUND: The therapeutic benefit of nerve decompression surgeries for chronic headache/migraine are controversial. AIM: To provide clinical characteristics of headache type and treatment outcome of occipital nerve decompression surgery. METHODS: A retrospective review of clinical records. Inclusion criteria were evidence of chronic occipital headache with and without migrainous features and tenderness of neck muscles, occipital allodynia, and inadequate response to prophylactic drugs. RESULTS: Surgical decompression of the greater and lesser occipital nerves provided complete and extended (3-6 years) relief of new daily persistent headache in case 3 (46 year old female), and of chronic post-traumatic headache in cases 4 and 6 (35 and 30 year old females, respectively), partial relief of chronic headache/migraine in cases 1 and 2 (41 year old female and 36 year old male), and no relief of episodic (cases 3 and 4) or chronic migraine (case 5, 52 year old male), or chronic tension-type headache (case 7, 31 year old male). CONCLUSIONS: As a case series, this study cannot test a hypothesis or determine cause and effect. However, the complete elimination of new daily persistent headache and post-traumatic headache, and the partial elimination of chronic headache/migraine in two patients - all refractory to other treatment approaches - supports and justifies the effort to continue to generate data that can help determine whether decompression nerve surgeries are beneficial in the treatment of certain types of chronic headache.

Selective Inhibition of Trigeminovascular Neurons by Fremanezumab: A Humanized Monoclonal Anti-CGRP Antibody.

A large body of evidence supports an important role for calcitonin gene-related peptide (CGRP) in migraine pathophysiology. This evidence gave rise to a global effort to develop a new generation of therapeutics that inhibit the interaction of CGRP with its receptor in migraineurs. Recently, a new class of such drugs, humanized anti-CGRP monoclonal antibodies (CGRP-mAbs), were found to be effective in reducing the frequency of migraine. The purpose of this study was to better understand how the CGRP-mAb fremanezumab (TEV-48125) modulates meningeal sensory pathways. To answer this question, we used single-unit recording to determine the effects of fremanezumab (30 mg/kg, IV) and its isotype control Ab on spontaneous and evoked activity in naive and cortical spreading depression (CSD)-sensitized trigeminovascular neurons in the spinal trigeminal nucleus of anesthetized male and female rats. The study demonstrates that, in both sexes, fremanezumab inhibited naive high-threshold (HT) neurons, but not wide-dynamic range trigeminovascular neurons, and that the inhibitory effects on the neurons were limited to their activation from the intracranial dura but not facial skin or cornea. In addition, when given sufficient time, fremanezumab prevents the activation and sensitization of HT neurons by CSD. Mechanistically, these findings suggest that HT neurons play a critical role in the initiation of the perception of headache and the development of cutaneous allodynia and central sensitization. Clinically, the findings may help to explain the therapeutic benefit of CGRP-mAb in reducing headaches of intracranial origin such as migraine with aura and why this therapeutic approach may not be effective for every migraine patient.SIGNIFICANCE STATEMENT Calcitonin gene-related peptide (CGRP) monoclonal antibodies (CGRP-mAbs) are capable of preventing migraine. However, their mechanism of action is unknown. In the current study, we show that, if given enough time, a CGRP-mAb can prevent the activation and sensitization of high-threshold (central) trigeminovascular neurons by cortical spreading depression, but not their activation from the skin or cornea, suggesting a potential explanation for selectivity to migraine headache, but not other pains, and a predominantly peripheral site of action.

Fremanezumab-A Humanized Monoclonal Anti-CGRP Antibody-Inhibits Thinly Myelinated (Aδ) But Not Unmyelinated (C) Meningeal Nociceptors.

Calcitonin gene-related peptide (CGRP), the most abundant neuropeptide in primary afferent sensory neurons, is strongly implicated in the pathophysiology of migraine headache, but its role in migraine is still equivocal. As a new approach to migraine treatment, humanized anti-CGRP monoclonal antibodies (CGRP-mAbs) were developed to reduce the availability of CGRP, and were found effective in reducing the frequency of chronic and episodic migraine. We recently tested the effect of fremanezumab (TEV-48125), a CGRP-mAb, on the activity of second-order trigeminovascular dorsal horn neurons that receive peripheral input from the cranial dura, and found a selective inhibition of high-threshold but not wide-dynamic range class of neurons. To investigate the basis for this selective inhibitory effect, and further explore the mechanism of action of CGRP-mAbs, we tested the effect of fremanezumab on the cortical spreading depression-evoked activation of mechanosensitive primary afferent meningeal nociceptors that innervate the cranial dura, using single-unit recording in the trigeminal ganglion of anesthetized male rats. Fremanezumab pretreatment selectively inhibited the responsiveness of Aδ neurons, but not C-fiber neurons, as reflected in a decrease in the percentage of neurons that showed activation by cortical spreading depression. These findings identify Aδ meningeal nociceptors as a likely site of action of fremanezumab in the prevention of headache. The selectivity in its peripheral inhibitory action may partly account for fremanezumab's selective inhibition of high-threshold, as a result of a predominant A-δ input to high-threshold neurons, but not wide dynamic-range dorsal horn neurons, and why it may not be effective in all migraine patients.SIGNIFICANCE STATEMENT Recently, we reported that humanized CGRP monoclonal antibodies (CGRP-mAbs) prevent activation and sensitization of high-threshold (HT) but not wide-dynamic range trigeminovascular neurons by cortical spreading depression (CSD). In the current paper, we report that CGRP-mAbs prevent the activation of Aδ but not C-type meningeal nociceptors by CSD. This is the first identification of an anti-migraine drug that appears to be selective for Aδ-fibers (peripherally) and HT neurons (centrally). As the main CGRP-mAb site of action appears to be situated outside the brain, we conclude that the initiation of the headache phase of migraine depends on activation of meningeal nociceptors, and that for selected patients, activation of the Aδ-HT pain pathway may be sufficient for the generation of headache perception.

Migraine photophobia originating in cone-driven retinal pathways.

Migraine headache is uniquely exacerbated by light. Using psychophysical assessments in patients with normal eyesight we found that green light exacerbates migraine headache significantly less than white, blue, amber or red lights. To delineate mechanisms, we used electroretinography and visual evoked potential recording in patients, and multi-unit recording of dura- and light-sensitive thalamic neurons in rats to show that green activates cone-driven retinal pathways to a lesser extent than white, blue and red; that thalamic neurons are most responsive to blue and least responsive to green; and that cortical responses to green are significantly smaller than those generated by blue, amber and red lights. These findings suggest that patients' experience with colour and migraine photophobia could originate in cone-driven retinal pathways, fine-tuned in relay thalamic neurons outside the main visual pathway, and preserved by the cortex. Additionally, the findings provide substrate for the soothing effects of green light.

[TECHNOLOGICAL SOLUTIONS FOR THE IMPROVEMENT OF OUTCOMES IN CARDIAC SURGERY OF OCTOGENARIAN PATIENTS].

INTRODUCTION: The current review addresses present-day technological advances in cardiac surgery performed on octogenarian patients, namely off-pump coronary artery bypass grafting (CABG), proximal anastomosis device, routine use of intraoperative epiaortic ultrasound, transcatheter aortic valve implantation (TAVI), and brain protection during cardiac surgery. Conflict of Interest: Gil Bolotin served as a scientific advisor for Cardiogard Ltd., which is addressed in this review paper.

Simvastatin and vitamin D for migraine prevention: A randomized, controlled trial.

OBJECTIVE: The aim of this work was to assess efficacy and tolerability of simvastatin plus vitamin D for migraine prevention in adults with episodic migraine. METHODS: We performed a randomized, double-blind, placebo-controlled trial with a 12-week baseline period and 24-week intervention period in 57 adults with episodic migraine. Participants were randomly assigned to simvastatin 20 mg tablets twice-daily plus vitamin D3 1,000 international units capsules twice-daily or matching placebo tablets and capsules. RESULTS: Compared to placebo, participants using simvastatin plus vitamin D3 demonstrated a greater decrease in number of migraine days from the baseline period to intervention weeks 1 to 12: a change of -8.0 (interquartile range [IQR]: -15.0 to -2.0) days in the active treatment group versus +1.0 (IQR: -1.0 to + 6.0) days in the placebo group, p < 0.001; and to intervention weeks 13 to 24: a change of -9.0 (IQR: -13 to -5) days in the active group versus +3.0 (IQR: -1.0 to + 5.0) days in the placebo group, p < 0.001. In the active treatment group, 8 patients (25%) experienced 50% reduction in the number of migraine days at 12 weeks and 9 (29%) at 24 weeks postrandomization. In comparison, only 1 patient (3%) in the placebo group (p = 0.03) experienced such a reduction. Adverse events were similar in both active treatment and placebo groups. INTERPRETATION: The results demonstrate that simvastatin plus vitamin D is effective for prevention of headache in adults with episodic migraine. Given statins' ability to repair endothelial dysfunction, this economical approach may also reduce the increased risk for vascular diseases among migraineurs.

Urinary concentration of cytokines in children with acute pyelonephritis.

Urinary tract infection (UTI) is a common bacterial infection among infants and children. Predicting which children with upper UTI will develop long-term sequelae remains difficult. We aimed at evaluating the predictive value of urine concentrations of interleukin-6 (UIL-6) and interleukin-8 (UIL-8) in subsequent renal scarring. In the current observational prospective study, urine samples for UIL-6 and UIL-8 were obtained from two groups: 31 children with first episode of febrile UTI and 22 febrile children of other origin. UIL-6 and UIL-8 were increased in children with febrile UTI, compared to children with fever of other origin [median and range (picograms per milliliter): (1) UIL-6, 74.46 (0-168) vs. 10.51 (0-47.50), respectively, p = 0.0001; (2) UIL-8, 2,660.38 (0-13,801) vs. 0, respectively, p = 0.0001]. Renal scarring was found in 5/31 (16 %) children with acute pyelonephritis. Initial median UIL-8 values were significantly higher in children with later renal scarring than in those without renal scarring [median and range (picograms per milliliter): 6,163 (2,021-13,801) vs. 1,490.5 (0-5,737), respectively, p = 0.018]. In conclusion, UIL-8 might serve as a predictive biomarker for renal scarring after an acute episode of pyelonephritis. Since UIL-8 emerges as a renal-specific diagnostic and prognostic marker, it may be suitable as a selective screening tool for children with febrile UTI.

Investigation of risks for cerebral embolism associated with the hemodynamics of cardiopulmonary bypass cannula: a numerical model.

Cerebral emboli originating in the ascending aorta are a major cause of noncardiac complications following cardiac surgery. The hemodynamics of the aortic cannula has been proven to play a significant role in emboli generation and distribution. The aim of the current study was to perform a thorough numerical investigation in order to examine the effect of the design and orientation of the cannula used during cardiopulmonary bypass on the risk to develop cerebral embolism. Hemodynamic analyses compared numerical models of 27 cases consisting of six different cannula orientations, four aortic anatomies, and three cannula designs. The cannula designs included a straight-tip (ST) cannula, a moderately curved tip cannula (TIP1 ), and a sharp-angle curved cannula (TIP2 ). Outcome measures included hemodynamic parameters such as emanating jet velocity, jet velocity drop, maximal shear stress, aortic wall reaction, emboli pathlines and distribution between upper and lower vessels, and stagnation regions. Based on these parameters, the risks for hemolysis, atheroembolism, and cerebral embolism were evaluated and compared. On one hand, the jet emerging from the ST cannula generated large wall-shear stress at the aortic wall; this may have triggered the erosion and distribution of embolic atheromatous debris from the aortic arch. On the other hand, it diverted more emboli from the clamp region to the descending aorta and thus reduced the risk for cerebral embolism. The TIP1 cannula demonstrated less shear stress on the aortic wall and diverted more emboli from the clamp region toward the upper vessels. The TIP2 cannula exhibited a stronger emanating jet, higher shear stress inside the cannula, and highly disturbed flow, which was more stagnant near the clamp region. Current findings support the significant impact of the cannula design and orientation on emboli generation and distribution. Specifically, the straight tip cannula demonstrated a reduced risk of cerebral embolism, which may be pivotal in the clinical setting.

Automated thermal imaging monitors the local response to cervical cancer brachytherapy.

Malignant tumors have high metabolic and perfusion rates, which result in a unique temperature distribution as compared to healthy tissues. Here, we sought to characterize the thermal response of the cervix following brachytherapy in women with advanced cervical carcinoma. Six patients underwent imaging with a thermal camera before a brachytherapy treatment session and after a 7-day follow-up period. A designated algorithm was used to calculate and store the texture parameters of the examined tissues across all time points. We used supervised machine learning classification methods (K Nearest Neighbors and Support Vector Machine) and unsupervised machine learning classification (K-means). Our algorithms demonstrated a 100% detection rate for physiological changes in cervical tumors before and after brachytherapy. Thus, we showed that thermal imaging combined with advanced feature extraction could potentially be used to detect tissue-specific changes in the cervix in response to local brachytherapy for cervical cancer.

Streptokinase fibrinolysis protocol: the advantages of a non-operative treatment for stage II pediatric empyema patients.

BACKGROUND: Pediatric empyema necessitates prompt resolution and early hospital discharge with minimal morbidity. However, the most effective treatment approach is not yet established. OBJECTIVES: To assess the efficacy of an intrapleural streptokinase washing protocol as a non-operative treatment for stage II pediatric empyema as compared to operative decortications, by the number of pediatric intensive care unit (PICU) admissions, length of PICU stay, and hospitalization duration. METHODS: We retrospectively evaluated 75 consecutive pediatric empyema cases for the period January 2006 to December 2009. Since July 2007 we have used repeated streptokinase-based pleural washing for stage II patients whose condition did not improve with chest drainage RESULTS: Before July 2007, 17 of 23 stage II empyema patients underwent decortication, compared to only 1 of 21 after July 2007. Non-operated children were admitted to the PICU less frequently than those who were operated (83% vs. 31%, p = 0.0006) and spent less time in the PICU (2.56 +/- 1.92 vs. 1.04 +/- 1.9 days, P= 0.0148); there was no significant statistical difference in overall hospitalization (13.33 +/- 3.69 vs.11.70 +/- 5.74 days, P= 0.301). CONCLUSIONS: Using intrapleural streptokinase washing as a non-operative treatment for stage II pediatric empyema yielded comparable success rates to the operative approach, with less morbidity.

[The learning curve of video-assisted thoracoscopic surgery (VATS) for lung lobectomy--a single Israeli center experience].

BACKGROUND: Video-assisted thoracoscopic surgery (VATS) is a method of lung lobe resection that has been implemented in medical centers worldwide since 1992. This procedure utilizes video equipment to assist in performing lobectomies without the need to open the chest wall As of 2009, VATS has been performed in the generaL thoracic surgery department of Rambam HeaLthcare Campus, Haifa. Since then, more than 200 patients were successfully operated on using this method. This study analyzed the Learning curve experienced by its surgeons and departmental staff since VATS implementation. METHODS: Patient files for all cases which underwent VATS in the department from January 2009 to June 2010 were retrospectively evaluated. The patients were divided into three groups based on their operation date; each group included patients that were operated on during a half-year interval. Data was collected and compared between the groups in regard to the percentage of surgeries that used VATS versus procedures which involved opening the chest wall, procedure time, duration of hospital stay, conversion ratios for closed to open operations, and intra and post-operative complications. Subsequent results were then compared to those reported from other countries around the world. RESULTS: VATS Lobectomies comprised the smallest percentage of the total Lobectomies performed in the department during the first 6 months of analysis (January 2009 - June 2009] as compared to the following year of analysis (July 2009 - June 2010), that involved a much more extensive use of VATS. The first 6 months of VATS implementation also involved fewer intra-operative complications and shorter operation times as compared to the following year. The length of stay and the number of post-operative complications were similar in each time interval analyzed. CONCLUSIONS: VATS lobectomy requires surgeons and departmental staff to face a steep learning curve. Operators should invest 6-12 months usage of VATS and perform 30-60 operations in order to achieve constant results that are consistent with those reported from other medical centers worldwide.

Advances in the Use of Electrospun Nanofibrous Polymeric Matrix for Dermal Healing at the Donor Site After the Split-Thickness Skin Graft Excision: A Prospective, Randomized, Controlled, Open-Label, Multicenter Study.

Dressings used to manage donor site wounds (DSWs) have up to 40% of patients experiencing complications that may cause suboptimal scarring. We evaluated the efficacy and safety of a portable electrospun nanofibrous matrix that provides contactless management of DSWs compared with standard dressing techniques. This study included adult patients who underwent an excised split-thickness skin graft (STSG) with a DSW area of 10 to 200 cm2. Patients were allocated into two groups; ie, the nanofiber group managed with a nanofibrous polymer-based matrix, and the control group managed using the standard of care such as Jelonet® or Biatain® Ibu dressing. Primary outcomes were postoperative dermal healing efficacy assessed by Draize scores. The time to complete re-epithelialization was also recorded. Secondary outcomes included postoperative adverse events, pain, and infections during the first 21 days and extended 12-month follow-up. The itching and scarring were recorded during the extended follow-up (months 1, 3, 6, 9, and 12) using Numerical-Analogue-Score and Vancouver scores, respectively. The nanofiber and control groups included 21 and 20 patients, respectively. The Draize dermal irritation scores were significantly lower in the nanofiber vs control group (Z = -2.509; P = .028) on the first postoperative day but became similar afterward (Z ≥ -1.62; P ≥ .198). In addition, the average time to re-epithelialization was similar in the nanofiber (17.9 ± 4.4 days) and control group (18.3 ± 4.5 days; Z = -0.299; P = .764), so were postoperative adverse events, pain, and infection incidence, itching and scarring. The safety and efficacy of electrospun nanofibrous matrix are similar to standard wound care allowing its use as an alternative donor site dressing following the STSG excision.

The migraine eye: distinct rod-driven retinal pathways' response to dim light challenges the visual cortex hyperexcitability theory.

Migraine-type photophobia, most commonly described as exacerbation of headache by light, affects nearly 90% of the patients. It is the most bothersome symptom accompanying an attack. Using subjective psychophysical assessments, we showed that migraine patients are more sensitive to all colors of light during ictal than during interictal phase and that control subjects do not experience pain when exposed to different colors of light. Based on these findings, we suggested that color preference is unique to migraineurs (as it was not found in control subjects) rather than migraine phase (as it was found in both phases). To identify the origin of this photophobia in migraineurs, we compared the electrical waveforms that were generated in the retina and visual cortex of 46 interictal migraineurs to those generated in 42 healthy controls using color-based electroretinography and visual-evoked potential paradigms. Unexpectedly, it was the amplitude of the retinal rod-driven b wave, which was consistently larger (by 14%-19% in the light-adapted and 18%-34% in the dark-adapted flash ERG) in the migraineurs than in the controls, rather than the retinal cone-driven a wave or the visual-evoked potentials that differs most strikingly between the 2 groups. Mechanistically, these findings suggest that the inherent hypersensitivity to light among migraine patients may originate in the retinal rods rather than retinal cones or the visual cortex. Clinically, the findings may explain why migraineurs complain that the light is too bright even when it is dim to the extent that nonmigraineurs feel as if they are in a cave.

Objective correlate of subjective pain perception by contact heat-evoked potentials.

UNLABELLED: The method of pain-evoked potentials has gained considerable acceptance over the last 3 decades regarding its objectivity, repeatability, and quantifiability. The present study explored whether the relationship between pain-evoked potentials and pain psychophysics obtained by contact heat stimuli is similar to those observed for the conventionally used laser stimulation. Evoked potentials (EPs) were recorded in response to contact heat stimuli at different body sites in 24 healthy volunteers. Stimuli at various temperatures were applied to the forearm (43 degrees C, 46 degrees C, 49 degrees C, and 52 degrees C) and leg (46 degrees C and 49 degrees C). The amplitudes of both components (N2 and P2) were strongly associated with the intensity of the applied stimuli and with subjective pain perception. Yet, regression analysis revealed pain perception and not stimulus intensity as the major contributing factor. A significant correlation was found between the forearm and the leg for both psychophysics and EPs amplitude. PERSPECTIVE: Contact heat can generate readily distinguishable evoked potentials on the scalp, consistent between upper and lower limbs. Although these potentials bear positive correlation with both stimulus intensity and pain magnitude, the latter is the main contributor to the evoked brain response.

Color-selective photophobia in ictal vs interictal migraineurs and in healthy controls.

Aversion to light is common among migraineurs undergoing acute attacks. Using psychophysical assessments in patients with episodic migraine, we reported that white, blue, amber, and red lights exacerbate migraine headache in a significantly larger percentage of patients and to a greater extent compared with green light. This study aimed at determining whether these findings are phase-dependent-namely, manifested exclusively during migraine (ictally) but not in its absence (interictally), or condition-dependent-ie, expressed uniquely in migraineurs but not in healthy controls. To determine whether the color preference of migraine-type photophobia is phase- or condition-dependent, we compared the effects of each color of light in each intensity between migraineurs during and in-between attacks and healthy controls. During the ictal and interictal phases, the proportion of migraineurs reporting changes in headache severity when exposed to the different colors of light increased in accordance with elevated light intensities. During the ictal phase, white, blue, amber, and red lights exacerbated headaches in ∼80% of the patients; however, during the interictal phase, light initiated headache in only 16% to 19%. Notably, green light exacerbated headaches in 40% and triggered headaches in 3% of the patients studied during the ictal and interictal phases, respectively. With one exception (highest red light intensity), no control subject reported headache in response to the light stimuli. These findings suggest that color preference is unique to migraineurs-as it was not found in control subjects-and that it is independent of whether or not the patients are in their ictal or interictal phase.

Psychological Factors and Conditioned Pain Modulation: A Meta-Analysis.

OBJECTIVE: Conditioned pain modulation (CPM) responses may be affected by psychological factors such as anxiety, depression, and pain catastrophizing; however, most studies on CPM do not address these relations as their primary outcome. The aim of this meta-analysis was to analyze the findings regarding the associations between CPM responses and psychological factors in both pain-free individuals and pain patients. MATERIALS AND METHODS: After a comprehensive PubMed search, 37 articles were found to be suitable for inclusion. Analyses used DerSimonian and Laird's random-effects model on Fisher's z-transforms of correlations; potential publication bias was tested using funnel plots and Egger's regression test for funnel plot asymmetry. Six meta-analyses were performed examining the correlations between anxiety, depression, and pain catastrophizing, and CPM responses in healthy individuals and pain patients. RESULTS: No significant correlations between CPM responses and any of the examined psychological factors were found. However, a secondary analysis, comparing modality-specific CPM responses and psychological factors in healthy individuals, revealed the following: (1) pressure-based CPM responses were correlated with anxiety (grand mean correlation in original units r=-0.1087; 95% confidence limits, -0.1752 to -0.0411); (2) heat-based CPM was correlated with depression (r=0.2443; 95% confidence limits, 0.0150 to 0.4492); and (3) electrical-based CPM was correlated with pain catastrophizing levels (r=-0.1501; 95% confidence limits, -0.2403 to -0.0574). DISCUSSION: Certain psychological factors seem to be associated with modality-specific CPM responses in healthy individuals. This potentially supports the notion that CPM paradigms evoked by different stimulation modalities represent different underlying mechanisms.

FDG PET/CT for assessing the resectability of NSCLC patients with N2 disease after neoadjuvant therapy.

OBJECTIVE: Neoadjuvant chemoradiotherapy (CMRT) is the most effective treatment of stage III non-small-cell lung cancer (NSCLC). The present study aimed at assessing FDG PET/CT for defining the response of N2 disease to neoadjuvant CMRT, as surgical resection after such therapy significantly improves 5-year survival in responding N2 disease. METHODS: Forty-five patients with locally advanced NSCLC underwent both pre-neoadjuvant therapy FDG PET/CT and post-neoadjuvant therapy FDG PET/CT followed by anatomical resection of lung and ipsilateral mediastinal lymph nodes (LN). Seventeen of these patients who had PET/CT studies in our institution and were operated after CMRT were retrospectively included in the study group (12 males, ages 43-78 years; stage IIIA: 14 patients, stage IIIB: 3 patients). PET/CT response in N2 was visually scored per-lymph node station and per patient. Quantitative N2 response was evaluated by SUVmax and total lesion glycolysis (TLG) measurements after therapy alone and in comparison with pre-therapy values. PET/CT N2 response was confirmed at surgery. RESULTS: Seventeen NSCLC patients with 29 metastatic N2 lymph nodes (LN) were assessed. Histopathology confirmed 14 responders and 3 non-responders, and was available in 20/29 metastatic LN, showing complete response in 17 and residual disease in 3 LN. LN-based visual analysis of N2 response on PET/CT defined 3 TP, 16 TN and 1 FP, for sensitivity, specificity, accuracy, negative and positive predictive values (NPV and PPV) of 100, 94, 95, 100 and 75%, respectively. Patient-based visual analysis defined 3 TP, 13 TN and 1 FP study, for sensitivity, specificity, accuracy, NPV and PPV of 100, 93, 94, 100 and 75%, respectively. Nodal-based quantitative analysis of FDG uptake in N2 nodes revealed a significant difference between responding and non-responding LN only of SUVmax post-therapy (2.5 ± 1.21 vs. 3.5 ± 2.36, P = 0.04). CONCLUSION: FDG PET/CT after neoadjuvant therapy accurately defined response in metastatic N2 nodes of NSCLC patients, presenting very high sensitivity and NPV for detecting responding nodes. PET/CT may enable selection of candidates for curative resection of stage III NSCLC. Mediastinoscopy may not be mandatory in patients with a negative PET/CT after neoadjuvant therapy.