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Malignant pleural effusion (MPE) from patients with advanced non-small-cell lung cancer (NSCLC) has been proven valuable for molecular analysis; however, simultaneous detection of driver fusions in MPE is still challenging. In this study, we investigated the Idylla™ GeneFusion Panel, a stand-alone test in tissue samples, in the evaluation of ALK , ROS1 , RET and MET ex14 skipping mutations in MPE and compared its performance with routine reference methods (Real-time-based and Next-generation Sequencing-NGS). The inclusion criteria for sample selection were as follows: advanced NSCLC harboring ALK , ROS1 , RET fusions or MET exon-skipping alterations and the availability of MPE collected at diagnosis or disease progression. Molecular alterations have been investigated on tissue by fluorescence in situ hybridization (FISH) or Real-time PCR or NGS. For molecular profiling with the Idylla™ GeneFusion, 200 µL of MPE supernatants combined with 50 µL of RNA Later solution were loaded into the Idylla™ cartridge without cfRNA extraction. The Idylla™ GeneFusion Assay performed on MPEs was able to confirm molecular profile, previously diagnosed with conventional methods, in all cases. Our data confirm that MPE are suitable material for investigating fusion alterations. The Idylla™ GeneFusion, although indicated for investigation of tissue samples, offers the possibility of performing a molecular characterization of supernatants without undertaking the entire cfRNA extraction procedure providing a rapid and reliable strategy for the detection of actionable genetic alterations.

Lung cancer remains the leading cause of cancer deaths worldwide. International societies have promoted the molecular analysis of MET proto-oncogene, receptor tyrosine kinase ( MET ) exon 14 skipping for the clinical stratification of non-small cell lung cancer (NSCLC) patients. Different technical approaches are available to detect MET exon 14 skipping in routine practice. Here, the technical performance and reproducibility of testing strategies for MET exon 14 skipping carried out in various centers were evaluated. In this retrospective study, each institution received a set ( n = 10) of a customized artificial formalin-fixed paraffin-embedded (FFPE) cell line (Custom MET ex14 skipping FFPE block) that harbored the MET exon 14 skipping mutation (Seracare Life Sciences, Milford, MA, USA), which was previously validated by the Predictive Molecular Pathology Laboratory at the University of Naples Federico II. Each participating institution managed the reference slides according to their internal routine workflow. MET exon 14 skipping was successfully detected by all participating institutions. Molecular analysis highlighted a median Cq cut off of 29.3 (ranging from 27.1 to 30.7) and 2514 (ranging from 160 to 7526) read counts for real-time polymerase chain reaction (RT-PCR) and NGS-based analyses, respectively. Artificial reference slides were a valid tool to harmonize technical workflows in the evaluation of MET exon 14 skipping molecular alterations in routine practice.

Background: The literature on upper limb robot-assisted therapy showed that robot-measured metrics can simultaneously predict registered clinical outcomes. However, only a limited number of studies correlated pre-treatment kinematics with discharge motor recovery. Given the importance of predicting rehabilitation outcomes for optimizing physical therapy, a predictive model for motor recovery that incorporates multidirectional indicators of a patient's upper limb abilities is needed. Objective: The aim of this study was to develop a predictive model for rehabilitation outcome at discharge (i.e., muscle strength assessed by the Motricity Index of the affected upper limb) based on multidirectional 2D robot-measured kinematics. Methods: Re-analysis of data from 66 subjects with subacute stroke who underwent upper limb robot-assisted therapy with an end-effector robot was performed. Two least squares error multiple linear regression models for outcome prediction were developed and differ in terms of validation procedure: the Split Sample Validation (SSV) model and the Leave-One-Out Cross-Validation (LOOCV) model. In both models, the outputs were the discharge Motricity Index of the affected upper limb and its sub-items assessing elbow flexion and shoulder abduction, while the inputs were the admission robot-measured metrics. Results: The extracted robot-measured features explained the 54% and 71% of the variance in clinical scores at discharge in the SSV and LOOCV validation procedures respectively. Normalized errors ranged from 22% to 35% in the SSV models and from 20% to 24% in the LOOCV models. In all models, the movement path error of the trajectories characterized by elbow flexion and shoulder extension was the significant predictor, and all correlations were significant. Conclusion: This study highlights that motor patterns assessed with multidirectional 2D robot-measured metrics are able to predict clinical evalutation of upper limb muscle strength and may be useful for clinicians to assess, manage, and program a more specific and appropriate rehabilitation in subacute stroke patients., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Goffredo, Proietti, Pournajaf, Galafate, Cioeta, Le Pera, Posteraro and Franceschini.)

(1) Background: In neurorehabilitation, Wearable Powered Exoskeletons (WPEs) enable intensive gait training even in individuals who are unable to maintain an upright position. The importance of WPEs is not only related to their impact on walking recovery, but also to the possibility of using them as assistive technology; however, WPE-assisted community ambulation has rarely been studied in terms of walking performance in real-life scenarios. (2) Methods: This study proposes the integration of an Inertial Measurement Unit (IMU) system to analyze gait kinematics during real-life outdoor scenarios (regular, irregular terrains, and slopes) by comparing the ecological gait (no-WPE condition) and WPE-assisted gait in five able-bodied volunteers. The temporal parameters of gait and joint angles were calculated from data collected by a network of seven IMUs. (3) Results: The results showed that the WPE-assisted gait had less knee flexion in the stance phase and greater hip flexion in the swing phase. The different scenarios did not change the human-exoskeleton interaction: only the low-speed WPE-assisted gait was characterized by a longer double support phase. (4) Conclusions: The proposed IMU-based gait assessment protocol enabled quantification of the human-exoskeleton interaction in terms of gait kinematics and paved the way for the study of WPE-assisted community ambulation in stroke patients.

Background: Overground Robot-Assisted Gait Training (o-RAGT) appears to be a promising stroke rehabilitation in terms of clinical outcomes. The literature on surface ElectroMyoGraphy (sEMG) assessment in o-RAGT is limited. This paper aimed to assess muscle activation patterns with sEMG in subjects subacute post stroke after training with o-RAGT and conventional therapy., Methods: An observational preliminary study was carried out with subjects subacute post stroke who received 15 sessions of o-RAGT (5 sessions/week; 60 min) in combination with conventional therapy. The subjects were assessed with both clinical and instrumental evaluations. Gait kinematics and sEMG data were acquired before (T1) and after (T2) the period of treatment (during ecological gait), and during the first session of o-RAGT (o-RAGT 1 ). An eight-channel wireless sEMG device acquired in sEMG signals. Significant differences in sEMG outcomes were found in the BS of TA between T1 and T2. There were no other significant correlations between the sEMG outcomes and the clinical results between T1 and T2., Conclusions: There were significant functional gains in gait after complex intensive clinical rehabilitation with o-RAGT and conventional therapy. In addition, there was a significant increase in bilateral symmetry of the Tibialis Anterior muscles. At this stage of the signals from the tibialis anterior (TA), gastrocnemius medialis (GM), rectus femoris (RF), and biceps femoris caput longus (BF) muscles of each lower extremity. sEMG data processing extracted the Bilateral Symmetry (BS), the Co-Contraction (CC), and the Root Mean Square (RMS) coefficients., Results: Eight of 22 subjects in the subacute stage post stroke agreed to participate in this sEMG study. This subsample demonstrated a significant improvement in the motricity index of the affected lower limb and functional ambulation. The heterogeneity of the subjects' characteristics and the small number of subjects was associated with high variability research, functional gait recovery was associated with minimal change in muscle activation patterns.

Background: Overground Robot-Assisted Gait Training (o-RAGT) provides intensive gait rehabilitation. This study investigated the efficacy of o-RAGT in subacute stroke subjects, compared to conventional gait training., Methods: A multicenter randomized controlled trial was conducted on 75 subacute stroke subjects (38 in the Experimental Group (EG) and 37 in the Control Group (CG)). Both groups received 15 sessions of gait training (5 sessions/week for 60 min) and daily conventional rehabilitation. The subjects were assessed at the beginning (T1) and end (T2) of the training period with the primary outcome of a 6 Minutes Walking Test (6MWT), the Modified Ashworth Scale of the Affected lower Limb (MAS-AL), the Motricity Index of the Affected lower Limb (MI-AL), the Trunk Control Test (TCT), Functional Ambulation Classification (FAC), a 10 Meters Walking Test (10MWT), the modified Barthel Index (mBI), and the Walking Handicap Scale (WHS)., Results: The 6MWT increased in both groups, which was confirmed by both frequentist and Bayesian analyses. Similar outcomes were registered in the MI-AL, 10MWT, mBI, and MAS-AL. The FAC and WHS showed a significant number of subjects improving in functional and community ambulation in both groups at T2., Conclusions: The clinical effects of o-RAGT were similar to conventional gait training in subacute stroke subjects. The results obtained in this study are encouraging and suggest future clinical trials on the topic.

Background: The limitation to the use of ElectroMyoGraphy (sEMG) in rehabilitation services is in contrast with its potential diagnostic capacity for rational planning and monitoring of the rehabilitation treatments, especially the overground Robot-Assisted Gait Training (o-RAGT). Objective: To assess the barriers to the implementation of a sEMG-based assessment protocol in a clinical context for evaluating the effects of o-RAGT in subacute stroke patients. Methods: An observational study was conducted in a rehabilitation hospital. The primary outcome was the success rate of the implementation of the sEMG-based assessment. The number of dropouts and the motivations have been registered. A detailed report on difficulties in implementing the sEMG protocol has been edited for each patient. The educational level and the working status of the staff have been registered. Each member of staff completed a brief survey indicating their level of knowledge of sEMG, using a five-point Likert scale. Results: The sEMG protocol was carried out by a multidisciplinary team composed of Physical Therapists (PTs) and Biomedical Engineers (BEs). Indeed, the educational level and the expertise of the members of staff influenced the fulfillment of the implementation of the study. The PTs involved in the study did not receive any formal education on sEMG during their course of study. The low success rate (22.7%) of the protocol was caused by several factors which could be grouped in: patient-related barriers; cultural barriers; technical barriers; and administrative barriers. Conclusions: Since a series of barriers limited the use of sEMG in the clinical rehabilitative environment, concrete actions are needed for disseminating sEMG in rehabilitation services. The sEMG assessment should be included in health systems regulations and specific education should be part of the rehabilitation professionals' curriculum. Clinical Trial Registration: www.ClinicalTrials.gov, identifier: NCT03395717., (Copyright © 2020 Goffredo, Infarinato, Pournajaf, Romano, Ottaviani, Pellicciari, Galafate, Gabbani, Gison and Franceschini.)

Background: Subjects with Down Syndrome (DS) are characterized by specific physiological alterations, including musculoskeletal abnormalities. Flat Foot (FF), caused by hypotonia and ligament laxity, represents one of the most common disabling disorders in this population. Conservative treatments promote the use of orthopaedic insoles and plantar supports. The aim of this study was to evaluate the impact of Foot Orthoses (FOs) on the gait pattern of subjects with DS, assessing the biomechanical effects associated with their use. Methods: Twenty-nine subjects were screened under two conditions-walking barefoot (WB); with shoes and insoles (WSI), during three trials for each. Assessments were performed through the 3D gait analysis, using an optoelectronic system, force platforms, and video recording. Specifically, synthetic indices of gait kinematics, i.e., gait profile score (GPS) and gait variable score (GVS) were calculated and compared with Wilcoxon signed-rank test, to evaluate between-conditions. Results: Significant variations were found in GVS foot progression index, representative of foot rotation during walking, in adolescents only. Conclusions: Bilateral FOs has a positive immediate impact on gait quality in adolescents with DS, as confirmed by quantitative analysis. FOs prescription is an evidence-based early approach to slow down biomechanical abnormalities and prevent relative symptoms.

This study aims to analyse the long-term effects (6 months follow-up) of upper limb Robot-assisted Therapy (RT) compared to Traditional physical Therapy (TT), in subacute stroke patients. Although the literature on upper-limb rehabilitation with robots shows increasing evidence of its effectiveness in stroke survivors, the length of time for which the re-learned motor abilities could be maintained is still understudied. A randomized controlled follow-up study was conducted on 48 subacute stroke patients who performed the upper-limb therapy using a planar end-effector robotic system (Experimental Group-EG) or TT (Control Group-CG). The clinical assessments were collected at T0 (baseline), T1 (end of treatment) and T2 (6 months follow-up): Upper Limb part of Fugl-Meyer assessment (FM-UL), total passive Range Of Motion (pROM), Modified Ashworth Scale Shoulder (MAS-S) and Elbow (MAS-E). At T1, the intra-group analysis showed significant gain of FM-UL in both EG and CG, while significant improvement in MAS-S, MAS-E, and pROM were found in the EG only. At T2, significant increase in MAS-S were revealed only in the CG. In FM-UL, pROM and MAS-E the improvements obtained at the end of treatment seem to be maintained at 6 months follow-up in both groups. The inter-groups analysis of FM-UL values at T1 and T2 demonstrated significant differences in favour of EG. In conclusion, upper limb Robot-assisted Therapy may lead a greater reduction of motor impairment in subacute stroke patients compared to Traditional Therapy. The gains observed at the end of treatment persisted over time. No serious adverse events related to the study occurred., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Background: Upper limb robot-assisted therapy (RT) provides intensive, repetitive, and task-specific treatment, and its efficacy for stroke survivors is well established in literature. Biomechanical data from robotic devices has been widely employed for patient's assessment, but rarely it has been analysed for tracking patient progress during RT. The goal of this retrospective study is to analyse built-in kinematic data registered by a planar end-effector robot for assessing the time course of motor recovery and patient's workspace exploration skills. A comparison of subjects having mild and severe motor impairment has been also conducted. For that purpose, kinematic data recorded by a planar end-effector robot have been processed for investigating how motor performance in executing point-to-point trajectories with different directions changes during RT., Methods: Observational retrospective study of 68 subacute stroke patients who conducted 20 daily sessions of upper limb RT with the InMotion 2.0 (Bionik Laboratories, USA): planar point-to-point reaching tasks with an "assist as needed" strategy. The following kinematic parameters (KPs) were computed for each subject and for each point-to-point trajectory executed during RT: movement accuracy, movement speed, number of peak speed, and task completion time. The Wilcoxon signed-rank tests were used with clinical outcomes. the Friedman test and post hoc Conover's test (Bonferroni's correction) were applied to KPs. A secondary data analysis has been conducted by comparing patients having different severities of motor impairment. The level of significance was set at p value < 0.05., Results: At the RT onset, the movements were less accurate and smoothed, and showed higher times of execution than those executed at the end of treatment. The analysis of the time course of KPs highlighted that RT seems to improve the motor function mainly in the first sessions of treatment: most KPs show significant intersession differences during the first 5/10 sessions. Afterwards, no further significant variations occurred. The ability to perform movements away from the body and from the hemiparetic side remains more challenging. The results obtained from the data stratification show significant differences between subjects with mild and severe motor impairment., Conclusion: Significant improvements in motor performance were registered during the time course of upper limb RT in subacute stroke patients. The outcomes depend on movement direction and motor impairment and pave the way to optimize healthcare resources and to design patient-tailored rehabilitative protocols., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2019 Michela Goffredo et al.)

Background: Although gait disorders strongly contribute to perceived disability in people with Parkinson's disease, clinical trials have failed to identify which task-oriented gait training method can provide the best benefit. Freezing of gait remains one of the least investigated and most troublesome symptoms., Objective: We aimed to compare the effects of robot-assisted gait training and treadmill training on endurance and gait capacity in people with Parkinson disease; the secondary aim was to compare the effect of the treatments in people with freezing and/or severe gait disability and assess changes in overall disease-related disability and quality of life., Methods: Outpatients with Parkinson disease (Hoehn and Yahr stage≥2) were randomly assigned to receive 20 sessions of 45-min gait training assisted by an end-effector robotic device (G-EO System) or treadmill training. Outcome assessments were the 6-min walk test, Timed Up and Go test, Freezing of Gait Questionnaire, Unified Parkinson's Disease Rating Scales and Parkinson's Disease Quality of Life Questionnaire-39 administered before (T0) and after treatment (T1)., Results: We included 96 individuals with Parkinson disease: 48 with robot-assisted gait training and 48 treadmill training. Both groups showed significant improvement in all outcomes. As compared with baseline, with robot-assisted gait training and treadmill training, endurance and gait capacity were enhanced by 18% and 12%, respectively, and motor symptoms and quality of life were improved by 17% and 15%. The maximum advantage was observed with the Freezing of Gait Questionnaire score, which decreased by 20% after either treatment. On post-hoc analysis, dependent walkers benefited more than independent walkers from any gait training, whereas freezers gained more from robot-assisted than treadmill training in terms of freezing reduction., Conclusions: Repetitive intensive gait training is an effective treatment for people with Parkinson disease and can increase endurance and gait velocity, especially for those with severe walking disability. Advantages are greater with robot-assisted gait training than treadmill training for individuals with freezing of gait - related disability., (Copyright © 2019 Elsevier Masson SAS. All rights reserved.)

Background: End-effector robots allow intensive gait training in stroke subjects and promote a successful rehabilitation. A comparison between conventional and end-effector Robot-Assisted Gait Training (RAGT) in subacute stroke patients is needed., Objective: To investigate the efficacy of end-effector RAGT in subacute stroke patients., Methods: Twenty-six subacute stroke patients were divided into two group: 14 patients performed RAGT (RG); 12 patients performed conventional gait training (CG). Clinical assessment and gait analysis were performed at the beginning (T0) and at the end (T1) of the rehabilitation., Results: The RG revealed a significant improvement in body function, activities, participation scales, and in the distance measured with the 6 MWT. The affected lower limb's spasticity significantly decreased at T1. In gait analysis, RG showed significantly increases in many parameters. The CG significantly improved clinical assessments but showed no significant changes in gait parameters. Statistically significant differences between RG and CG were found in MRC-HE, TCT, 10 MWT, 6 MWT, and TUG. No significant difference between groups was registered in gait kinematics., Conclusions: Both rehabilitation treatments produce promising effects in subacute stroke patients. RAGT device offers a more intensive, controlled, and physiological gait training and significantly improved deambulation.

Background: Upper limb recovery is one of the main goals of post-stroke rehabilitation due to its importance for autonomy in Activities of Daily Living (ADL). Although the efficacy of upper limb Robot-assisted Therapy (RT) is well established in literature, the impact of the initial status of the patient on the effects of RT is still understudied. This paper aims to identify whether demographic, clinical and motor characteristics of stroke patients may influence the ability to independently perform ADL after RT., Methods: A retrospective study was conducted on sixty stroke patients who conducted planar upper limb goal-directed tasks with the InMotion 2.0 robot. The RT was administered 5 days/week for 4 weeks and each session lasted 45 minutes. The primary outcome measure was the Modified Barthel Index (BI), dichotomized into favourable (BI ≥75) and unfavourable (BI<75) outcomes. The potential predictors were the demographic and clinical records, and the following clinical assessment scores: Modified Ashworth Scale-Shoulder (MAS-S); Modified Ashworth Scale-Elbow (MAS-E); Fugl-Meyer Assessment Upper Extremity (FMA-UE); upper limb section of the Motricity Index (MIul); total passive Range Of Motion (pROM); and Box and Block Test (BBT)., Results: Statistical analysis showed that the BBT, FMA-UE and MIul scores were significant predictors of a favourable outcome in ADL. The cut-off scores of the independent variables were calculated (FMA-UE = 32; MIul = 48; BBT = 3) with respect to the dichotomic BI outcome. Their robustness was assessed with the Fragility Index (FMA-UE = 2; MIul = 3; BBT = 7), showing that BBT is the most robust predictor of favourable BI outcome. Moreover, subjects with all predictors higher than the cut-off scores had higher probability to increase their independence in ADL at the end of the therapy. Demographic records, spasticity and pROM were not identified as predictors., Conclusion: Stroke patients with greater manual dexterity and less impairment appear to have a higher probability of achieving clinically significant ADL outcomes after upper limb RT. The obtained results can help to optimise the management of RT treatment planning. Further studies on a larger number of patients with a long-term follow up are recommended in order to evaluate other potential predictors and to validate the results.

Background: The gait recovery is a realist goal in the rehabilitation of almost Stroke patients. Over the last years, the introduction of robotic technologies in gait rehabilitation of stroke patients has had a greatest interest., Objective: The aim of this study was to evaluate efficacy of Robotic Gait Training (RGT) in chronic stroke patients., Methods: Fourteen chronic stroke patients were divided into two groups. Six patients received RGT, eight patients received traditional gait rehabilitation. Patients were assessed with clinical scales, as well as with gait analysis, at the beginning and at the end of the treatment., Results: Significant changes in some clinical scales for both the groups were detected. In the robotic group, patients showed higher percentage changes in the MRC scale (p = 0.020), in the 6MWT (p = 0.043) and in the Ashworth scale (hip: p = 0.008; knee: p = 0.043; ankle: p = 0.043) when compared with the traditional group. With respect to the gait analysis, we did not found any difference neither in the within-group analysis, nor in the between-group analysis., Conclusions: Both rehabilitation treatments do not change the compensatory strategies in chronic patients but the RGT offers to the patients a more intensive and controlled gait training increasing the gait endurance and decreasing spasticity in the lower limb.

In the last few years, not many studies on the use of robot-assisted therapy to recover hand function in acute stroke patients have been carried out. This randomized-controlled observer trial is aimed at evaluating the effects of intensive robot-assisted hand therapy compared with intensive occupational therapy in the early recovery phases after stroke with a 3-month follow-up. Twenty acute stroke patients at their first-ever stroke were enrolled and randomized into two groups. The experimental treatment was performed using the Amadeo Robotic System. Control treatment, instead, was carried out using occupational therapy executed by a trained physiotherapist. All participants received 20 sessions of treatment for 4 consecutive weeks (5 days/week). The following clinical scales, Fugl-Meyer Scale (FM), Medical Research Council Scale for Muscle Strength (hand flexor and extensor muscles) (MRC), Motricity Index (MI) and modified Ashworth Scale for wrist and hand muscles (MAS), were performed at baseline (T0), after 20 sessions (end of treatment) (T1) and at the 3-month follow-up (T2). The Barthel Index was assessed only at T0 and T1. Evidence of a significant improvement was shown by the Friedman test for the FM [experimental group (EG): P=0.0039, control group (CG): P<0.0001], Box and Block Test (EG: P=0.0185, CG: P=0.0086), MI (EG: P<0.0001, CG: P=0.0303) and MRC (EG: P<0.0001, CG: P=0.001) scales. These results provide further support to the generalized therapeutic impact of intensive robot-assisted treatment on hand recovery functions in individuals with acute stroke. The robotic rehabilitation treatment may contribute toward the recovery of hand motor function in acute stroke patients. The positive results obtained through the safe and reliable robotic rehabilitation treatment reinforce the recommendation to extend it to a larger clinical practice.

Background and Purpose: Progressive supranuclear palsy (PSP) is a rare neurodegenerative disease clinically characterized by prominent axial extrapyramidal motor symptoms with frequent falls. Over the last years the introduction of robotic technologies to recover lower limb function has been greatly employed in the rehabilitative practice. This observational trial is aimed at investigating the changes in the main spatiotemporal following end-effector robot training in people with PSP., Method: Pilot observational trial., Participants: Five cognitively intact participants with PSP and gait disorders., Interventions: Patients were submitted to a rehabilitative program of robot-assisted walking sessions for 45 min, 5 times a week for 4 weeks., Main Outcome Measures: The spatiotemporal parameters at the beginning (T0) and at the end of treatment (T1) were recorded by a gait analysis laboratory., Results: Robot training was feasible, acceptable and safe and all participants completed the prescribed training sessions. All patients showed an improvement in the gait spatiotemporal index (Mean velocity, Cadence, Step length, and Step width) (T0 vs. T1)., Conclusions: Robot training is a feasible and safe form of rehabilitation for cognitively intact people with PSP. The lack of side effects and the positive results in the gait parameter index in all patients support the recommendation to extend the trials of this treatment. Further investigation regarding the effectiveness of robot training in time is necessary., Trial Registration: ClinicalTrials.gov NCT01668407.

Background: We have previously demonstrated that expression of COX-2 is upregulated by hepatocyte growth factor in thyroid papillary carcinoma (TPC) cells and is associated with increased invasiveness of tumor cells. COX-2 upregulation was associated with downregulation of KAI-1/CD82, a metastasis suppressor molecule that has been associated with the metastatic potential of several solid tumors. In the present study, we have investigated the possibility that downregulation of KAI-1/CD82 may contribute to the invasiveness of papillary carcinoma cells., Methods: Expression of KAI-1/CD82 and its relation to COX-2 levels were investigated in 6 primary cultures of TPC, in 2 tumor cell lines (TPC-1 and K1), and in 55 tumor samples of TPC. The biological role of KAI-1/CD82 in regulating tumor invasiveness was investigated in TPC cell lines and primary cultures transfected with a pCDNA3.1/Hygro.KAI-1; transfected cells were tested in functional studies of cell migration and invasiveness. Finally, the role of KAI-1/CD82 in influencing TPC metastasis was investigated in vivo using nu/nu mice injected with K1-transfected cells., Results: We provide evidence that COX-2 and KAI-1/CD82 are inversely regulated in TPC primary cultures and in TPC-1 tumor cells. In fact, inhibition of COX-2 with NS398 is associated with a 2-9-fold upregulation of KAI-1/CD82 RNA. Moreover, a possible relation between COX-2 and KAI-1/CD82 was confirmed by the presence of a statistically significant inverse correlation in the expression of the two genes in 55 tumor samples of TPC (r = -0.513; p = 0.001). In 36 of 55 cases, tumor areas contained lower levels of KAI-1/CD82 RNA as compared with the corresponding normal tissue. Low expression of KAI-1/CD82 RNA in the tumor area was associated with extrathyroid extension of the disease in 16 of 19 cases (p < 0.04) and with lymph node metastasis in 11 of 14 cases (not significant). KAI-1/CD82 re-expression in tumor cells was associated with a significant decrease in their migratory (50-76% reduction) and invasive (46-65% reduction) capacity, even after hepatocyte growth factor stimulation. Finally, nu/nu mice injected with KAI-1/CD82-transfected K1 TPC cells developed fewer and smaller metastasis as compared with mice injected with vector-transfected K1 cells (p=0.016)., Conclusion: Our findings raise the possibility that downregulation of KAI-1/CD82 in TPC cells is one of the molecular mechanisms regulating their invasive and metastatic potential.