CT-guided pretreatment biopsy diagnosis in patients with thymic epithelial tumours: diagnostic accuracy and risk of seeding.

AIM: To investigate the diagnostic performance of computed tomography (CT)-guided percutaneous transthoracic needle biopsy (PTNB) for thymic epithelial tumours (TETs) and the complication rate after PTNB including seeding after PTNB. MATERIALS AND METHODS: This retrospective study identified PTNBs for anterior mediastinal lesions between May 2007 and September 2021. The diagnostic performance for TETs and complications were investigated. The concordance of the histological grades of TETs between PTNB and surgery was evaluated. The factors associated with pleural seeding after PTNB were determined using Cox regression analysis. RESULTS: Of 387 PTNBs, 235 PTNBs from 225 patients diagnosed as TETs (124 thymomas and 101 thymic carcinomas) and 150 PTNBs from 133 patients diagnosed as other than TETs were included. The sensitivity, specificity, and accuracy for TETs were 89.4% (210/235), 100% (210/210), and 93.5% (360/385), respectively, with an immediate complication rate of 4.4% (17/385). The concordance rate of the histological grades between PTNB and surgery was 73.3% (77/105) after excluding uncategorised types of thymomas. During follow-up after PTNB (median duration, 38.8 months; range, 0.3-164.6 months), no tract seeding was observed. Pleural seeding was observed in 26 patients. Thymic carcinoma (hazard ratio [HR], 5.94; 95% confidence interval [CI], 2.07-17.08; p=0.001) and incomplete resection (HR, 3.29; 95% CI, 1.20-9.02; p=0.02) were associated with pleural seeding, while the biopsy approach type (transpleural versus parasternal) was not associated (p=0.12). CONCLUSIONS: Pretreatment biopsy for TETs was accurate and safe and may be considered for diagnosing TETs, particularly when the diagnosis is challenging and histological diagnosis is mandatory.

Knee Recurvatum in Children With Spastic Diplegic Cerebral Palsy.

BACKGROUND: The purpose of this study is to determine which factors drive patients with diplegic cerebral palsy to walk without knee recurvatum despite hyperextension of the knee on physical examination. METHODS: A retrospective review was conducted of all data collected in the Gait Analysis Laboratory between 1999 and 2014. Patients with spastic diplegic cerebral palsy and at least 5 degrees of knee extension on clinical examination were identified for the study. After IRB approval, a total of 60 children ranging in age from 4 to 17 were included in the study. There were 27 female patients. Gross Motor Function Classification System level was distributed in the population as follows: 34 patients at Gross Motor Function Classification System level I, 18 at level II, and 8 at level III. Patients were excluded from this study if they had extrapyramidal involvement, history of selective dorsal rhizotomy or lower extremity surgery. Patient who received botulinum toxin A injections within 1 year of the study were excluded as well. Patients were divided into 2 groups: children that walked with knee hyperextension (KH) and children that walked without knee hyperextension (KF, "knee flexion"). There were 15 subjects in the KH group and 45 subjects in the KF group. Motion Laboratory evaluation included a comprehensive examination, kinematics, and kinetic analysis with a VICOM system. All data were analyzed with unpaired t test to detect differences between the 2 groups. All statistical analysis was done only for the right legs (unless the right leg did not meet the exclusion then the left leg was analyzed) to meet the statistical requirement for independence. The Pearson correlation was applied to correlate the maximum knee extension in stance with maximum ankle dorsiflexion in stance. RESULTS: The static measurement of dorsiflexion with knee flexed showed statistically significant difference (P=0.004) with KH group having 2.3±11.6 degrees and KF group having 13.1±12.2 degrees. There was also a statistically significant difference in the static measurement of dorsiflexion with knee extended (P=0.0014) with KH group having -3.3±9.0 degrees and KF group having 5.8±9.1 degrees. Maximum dorsiflexion in stance phase also showed significant difference (P=0.0022) with the KH group having 0.1±14.0 degrees and KF group having 11.5±11.2 degrees. Maximum dorsiflexion in stance phase also showed significant difference (P<0.001) with the DH group having 0.1 (SD) 14.0 degrees and KF group having 11.5 (SD) 11.2 degrees. There were no significant differences in popliteal angle measurements or any strength measurement. CONCLUSIONS: Our study shows that the plantar flexion knee extension couple is the major contributing factor to cause patients with passive knee hyperextension to walk in a recurvatum pattern. This would have implications of further treatment of the knee hyperextension in stance. LEVEL OF EVIDENCE: Level III-case-control study.

Nrf2-dependent persistent oxidative stress results in stress-induced vulnerability to depression.

Stressful life events produce a state of vulnerability to depression in some individuals. The mechanisms that contribute to vulnerability to depression remain poorly understood. A rat model of intense stress (social defeat (SD), first hit) produced vulnerability to depression in 40% of animals. Only vulnerable animals developed a depression-like phenotype after a second stressful hit (chronic mild stress). We found that this vulnerability to depression resulted from a persistent state of oxidative stress, which was reversed by treatment with antioxidants. This persistent state of oxidative stress was due to low brain-derived neurotrophic factor (BDNF) levels, which characterized the vulnerable animals. We found that BDNF constitutively controlled the nuclear translocation of the master redox-sensitive transcription factor Nrf2, which activates antioxidant defenses. Low BDNF levels in vulnerable animals prevented Nrf2 translocation and consequently prevented the activation of detoxifying/antioxidant enzymes, ultimately resulting in the generation of sustained oxidative stress. Activating Nrf2 translocation restored redox homeostasis and reversed vulnerability to depression. This mechanism was confirmed in Nrf2-null mice. The mice displayed high levels of oxidative stress and were inherently vulnerable to depression, but this phenotype was reversed by treatment with antioxidants. Our data reveal a novel role for BDNF in controlling redox homeostasis and provide a mechanistic explanation for post-stress vulnerability to depression while suggesting ways to reverse it. Because numerous enzymatic reactions produce reactive oxygen species that must then be cleared, the finding that BDNF controls endogenous redox homeostasis opens new avenues for investigation.

Nrf2-dependent persistent oxidative stress results in stress-induced vulnerability to depression.

This corrects the article DOI: 10.1038/mp.2016.144.

Oxidative stress-driven parvalbumin interneuron impairment as a common mechanism in models of schizophrenia.

Parvalbumin inhibitory interneurons (PVIs) are crucial for maintaining proper excitatory/inhibitory balance and high-frequency neuronal synchronization. Their activity supports critical developmental trajectories, sensory and cognitive processing, and social behavior. Despite heterogeneity in the etiology across schizophrenia and autism spectrum disorder, PVI circuits are altered in these psychiatric disorders. Identifying mechanism(s) underlying PVI deficits is essential to establish treatments targeting in particular cognition. On the basis of published and new data, we propose oxidative stress as a common pathological mechanism leading to PVI impairment in schizophrenia and some forms of autism. A series of animal models carrying genetic and/or environmental risks relevant to diverse etiological aspects of these disorders show PVI deficits to be all accompanied by oxidative stress in the anterior cingulate cortex. Specifically, oxidative stress is negatively correlated with the integrity of PVIs and the extracellular perineuronal net enwrapping these interneurons. Oxidative stress may result from dysregulation of systems typically affected in schizophrenia, including glutamatergic, dopaminergic, immune and antioxidant signaling. As convergent end point, redox dysregulation has successfully been targeted to protect PVIs with antioxidants/redox regulators across several animal models. This opens up new perspectives for the use of antioxidant treatments to be applied to at-risk individuals, in close temporal proximity to environmental impacts known to induce oxidative stress.

A randomized phase 2 study of MK-2206 versus everolimus in refractory renal cell carcinoma.

Background: Activation of the phosphoinisitide-3 kinase (PI3K) pathway through mutation and constitutive upregulation has been described in renal cell carcinoma (RCC), making it an attractive target for therapeutic intervention. We performed a randomized phase II study in vascular endothelial growth factor (VEGF) therapy refractory patients to determine whether MK-2206, an allosteric inhibitor of AKT, was more efficacious than the mammalian target of rapamycin inhibitor everolimus. Patients and methods: A total of 43 patients were randomized in a 2:1 distribution, with 29 patients assigned to the MK-2206 arm and 14 to the everolimus arm. Progression-free survival (PFS) was the primary endpoint. Results: The trial was closed at the first futility analysis with an observed PFS of 3.68 months in the MK-2206 arm and 5.98 months in the everolimus arm. Dichotomous response rate profiles were seen in the MK-2206 arm with one complete response and three partial responses in the MK-2206 arm versus none in the everolimus arm. On the other hand, progressive disease was best response in 44.8% of MK2206 versus 14.3% of everolimus-treated patients. MK-2206 induced significantly more rash and pruritis than everolimus, and dose reduction occurred in 37.9% of MK-2206 versus 21.4% of everolimus-treated patients. Genomic analysis revealed that 57.1% of the patients in the PD group had either deleterious TP53 mutations or ATM mutations or deletions. In contrast, none of the patients in the non-PD group had TP53 or ATM defects. No predictive marker for response was observed in this small dataset. Conclusions: Dichotomous outcomes are observed when VEGF therapy refractory patients are treated with MK-2206, and MK-2206 does not demonstrate superiority to everolimus. Additionally, mutations in DNA repair genes are associated with early disease progression, indicating that dysregulation of DNA repair is associated with a more aggressive tumor phenotype in RCC.

Utility of 18F-fluoroestradiol (18F-FES) PET/CT imaging as a pharmacodynamic marker in patients with refractory estrogen receptor-positive solid tumors receiving Z-endoxifen therapy.

BACKGROUND: Z-endoxifen is the most potent of the metabolites of tamoxifen, and has the potential to be more effective than tamoxifen because it bypasses potential drug resistance mechanisms attributable to patient variability in the expression of the hepatic microsomal enzyme CYP2D6. 18F-FES is a positron emission tomography (PET) imaging agent which selectively binds to estrogen receptor alpha (ER-α) and has been used for non-invasive in vivo assessment of ER activity in tumors. This study utilizes 18F-FES PET imaging as a pharmacodynamic biomarker in patients with ER+ tumors treated with Z-endoxifen. METHODS: Fifteen patients were recruited from a parent therapeutic trial of Z-endoxifen and underwent imaging with 18F-FES PET at baseline. Eight had positive lesions on the baseline scan and underwent follow-up imaging with 18F-FES 1-5 days post administration of Z-endoxifen. RESULTS: Statistically significant changes (p = 0.0078) in standard uptake value (SUV)-Max were observed between the baseline and follow-up scans as early as 1 day post drug administration. CONCLUSION: F-FES PET imaging could serve as a pharmacodynamic biomarker for patients treated with ER-directed therapy.

Relationship between mental health risk factors and oral symptoms in adolescents: Korea Youth Risk Behavior Web-based Survey, 2013.

OBJECTIVE: To investigate the relationship between mental health risk factors and Korean adolescents' oral health. BASIC RESEARCH DESIGN: Cross-sectional study was based on the 9th Korea Youth Risk Behavior Web-based Survey (2013). PARTICIPANTS: Data were selected for 66,951 adolescents (33,777 males and 33,174 females; aged 13-18 years) out of 72,435 participants were analysed, after excluding cases with missing values. MAIN OUTCOME MEASURES: Oral health (experience of one or more of six oral symptoms), demographic characteristics (seven factors), and mental health risk (five factors). METHOD: Logistic regression analysis determined the effects of mental health risk factors on subjects' oral symptoms after adjustment for general characteristics. RESULTS: The adjusted odds ratio (AOR) was 1.52 (95%CI 1.50,1.54) for sleep satisfaction self-described as "not sufficient at all" and AOR 2.64 (95%CI 2.59,2.69) for those reporting very high stress levels. The AOR was 1.26 times (95%CI 1.24,1.27) higher for those using the internet on weekends for non-study purposes for ⟩6 hours than those using it for one hour. The AOR for experiencing oral symptoms was 1.44 times (95%CI 1.41,1.47) higher for those who had experienced school violence than for those who had not. CONCLUSIONS: Mental health risk factors were associated with oral symptoms. These results should inform the development of school health policies and comprehensive adolescent health promotion programs in Korea.

Association between excessive Internet use and oral health behaviors of Korean adolescents: A 2015 national survey.

OBJECTIVE: This study aimed to investigate excessive Internet use's (EIU's) association with oral health behaviors among Korean adolescents. BASIC RESEARCH DESIGN: This cross-sectional study was based on the 11th Korea Youth Risk Behavior Web-based Survey (2015). PARTICIPANTS: 68,043 school students aged 13-18 years (35,204 boys and 32,839 girls). Data on, 45,271 (23,354 males and 21,917 females using the Internet on weekdays) and 49,324 (27,448 males and 21,876 females using the Internet on weekends) were analyzed after excluding questionnaires with missing values. MAIN OUTCOME MEASURES: The key variables were oral health behaviors (tooth-brushing frequency and tooth brushing after lunch at school, and preventive oral health behaviors), EIU (hours of Internet use on weekdays and weekends, excluding use for academic purposes). RESULTS: Compared to the general groups, the odds ratio (OR) for less tooth-brushing was 4.04 (95%CI=2.990-5.459) and 3.55-fold higher (95% CI=2.703-4.659) in the high-risk groups for weekday and weekend EIU, respectively. For post-lunch tooth-brushing, compared to the general groups, the OR for less tooth-brushing was 1.7-fold higher in the high-risk groups for EIU during weekdays and weekends. The OR for no preventive behavior was significantly higher in the high-risk groups than in the potential-risk and general groups. CONCLUSIONS: Policies moderating adolescents' EIU may enable appropriate oral health behaviors.

Comparison of Rectus Femoris Transfer Surgery Done Concomitant With Hamstring Lengthening or Delayed in Patients With Cerebral Palsy.

BACKGROUND: Children with spastic cerebral palsy frequently develop stiff knee gait. A common treatment of flexed knee gait is lengthening of the hamstring tendons. It has been shown that minimum knee extension improves after hamstring surgeries. However, it has been observed that a decreased peak knee flexion in swing may be a complication of hamstring lengthening (HSL). This has been noted to occur because of an overactive rectus femoris during the swing phase of gait. A common treatment of decreased knee flexion in swing is distal rectus femoris transfer (DRFT). The purpose of this study is to compare the differences between doing DRFT concomitantly with HSL and doing delayed DRFT after HSL. METHODS: A total of 111 children with cerebral palsy (74 males and 37 females) who underwent HSL were reviewed retrospectively. All patients who met the inclusion criteria were divided into 3 groups, 28 subjects in the HSL alone group (H), 57 subjects in the HSL with concomitant rectus femoris transfer group (C), and 26 subjects in the HSL with delayed rectus femoris transfer group (D). RESULTS: The groups had similar minimum knee flexion in stance preoperatively and postoperatively. Group D's minimum knee flexion in stance improved to 5.5±12.7 degrees after HSL, but increased to 8.8±11.6 degrees after DRFT. Groups D and H had statistically significant reduction in maximum knee flexion in swing after HSL (P<0.05). Maximum knee flexion in swing was statistically significantly reduced in the D group after DRFT (P<0.05), but the C group was not statistically different from preoperative after DRFT (P>0.05). The C and D groups had similar total knee excursion postoperatively. The H group had less knee excursion than the other 2 groups, but it was not significant. CONCLUSIONS: The group that had DRFT concomitantly with HSL maintained maximum knee flexion in swing phase postoperatively. Although the group that had delayed DRFT had a reduction in maximum knee flexion after isolated HSL, gains in swing phase motion were achieved after delayed DRFT (comparable to that of the simultaneous group). LEVEL OF EVIDENCE: Level II.

Tollip, an early regulator of the acute inflammatory response in the substantia nigra.

BACKGROUND: Tollip is a ubiquitously expressed protein, originally described as a modulator of the IL-1R/TLR-NF-κB signaling pathways. Although this property has been well characterized in peripheral cells, and despite some evidence of its expression in the central nervous system, the role of Tollip in neuroinflammation remains poorly understood. The present study sought to explore the implication of Tollip in inflammation in the substantia nigra pars compacta, the structure affected in Parkinson's disease. METHODS: We first investigated Tollip distribution in the midbrain by immunohistochemistry. Then, we addressed TLR4-mediated response by intra-nigral injections of lipopolysaccharide (LPS), a TLR4 agonist, on inflammatory markers in Tollip knockout (KO) and wild-type (WT) mice. RESULTS: We report an unexpectedly high Tollip immunostaining in dopaminergic neurons of the mice brain. Second, intra-nigral injection of LPS led to increased susceptibility to neuroinflammation in Tollip KO compared to Tollip WT mice. This was demonstrated by a significant increase of tumor necrosis factor alpha (TNF-α), interleukin 1 beta (IL-1ß), interleukin 6 (IL-6), and interferon gamma (IFN-γ) messenger RNA (mRNA) in the midbrain of Tollip KO mice upon LPS injection. Consistently, brain rAAV viral vector transduction with a nuclear factor kappa B (NF-κB)-inducible reporter gene confirmed increased NF-κB activation in Tollip KO mice. Lastly, Tollip KO mice displayed higher inducible NO synthase (iNOS) production, both at the messenger and protein level when compared to LPS-injected WT mice. Tollip deletion also aggravated LPS-induced oxidative and nitrosative damages, as indicated by an increase of 8-oxo-2'-deoxyguanosine and nitrotyrosine immunostaining, respectively. CONCLUSIONS: Altogether, these findings highlight a critical role of Tollip in the early phase of TLR4-mediated neuroinflammation. As brain inflammation is known to contribute to Parkinson's disease, Tollip may be a potential target for neuroprotection.

Cortical fast-spiking parvalbumin interneurons enwrapped in the perineuronal net express the metallopeptidases Adamts8, Adamts15 and Neprilysin.

The in situ hybridization Allen Mouse Brain Atlas was mined for proteases expressed in the somatosensory cerebral cortex. Among the 480 genes coding for protease/peptidases, only four were found enriched in cortical interneurons: Reln coding for reelin; Adamts8 and Adamts15 belonging to the class of metzincin proteases involved in reshaping the perineuronal net (PNN) and Mme encoding for Neprilysin, the enzyme degrading amyloid ß-peptides. The pattern of expression of metalloproteases (MPs) was analyzed by single-cell reverse transcriptase multiplex PCR after patch clamp and was compared with the expression of 10 canonical interneurons markers and 12 additional genes from the Allen Atlas. Clustering of these genes by K-means algorithm displays five distinct clusters. Among these five clusters, two fast-spiking interneuron clusters expressing the calcium-binding protein Pvalb were identified, one co-expressing Pvalb with Sst (PV-Sst) and another co-expressing Pvalb with three metallopeptidases Adamts8, Adamts15 and Mme (PV-MP). By using Wisteria floribunda agglutinin, a specific marker for PNN, PV-MP interneurons were found surrounded by PNN, whereas the ones expressing Sst, PV-Sst, were not.

Glutathione deficit impairs myelin maturation: relevance for white matter integrity in schizophrenia patients.

Schizophrenia pathophysiology implies both abnormal redox control and dysconnectivity of the prefrontal cortex, partly related to oligodendrocyte and myelin impairments. As oligodendrocytes are highly vulnerable to altered redox state, we investigated the interplay between glutathione and myelin. In control subjects, multimodal brain imaging revealed a positive association between medial prefrontal glutathione levels and both white matter integrity and resting-state functional connectivity along the cingulum bundle. In early psychosis patients, only white matter integrity was correlated with glutathione levels. On the other side, in the prefrontal cortex of peripubertal mice with genetically impaired glutathione synthesis, mature oligodendrocyte numbers, as well as myelin markers, were decreased. At the molecular levels, under glutathione-deficit conditions induced by short hairpin RNA targeting the key glutathione synthesis enzyme, oligodendrocyte progenitors showed a decreased proliferation mediated by an upregulation of Fyn kinase activity, reversed by either the antioxidant N-acetylcysteine or Fyn kinase inhibitors. In addition, oligodendrocyte maturation was impaired. Interestingly, the regulation of Fyn mRNA and protein expression was also impaired in fibroblasts of patients deficient in glutathione synthesis. Thus, glutathione and redox regulation have a critical role in myelination processes and white matter maturation in the prefrontal cortex of rodent and human, a mechanism potentially disrupted in schizophrenia.

Childhood sexual and physical abuse: age at exposure modulates impact on functional outcome in early psychosis patients.

BACKGROUND: Evidence suggests a relationship between exposure to trauma during childhood and functional impairments in psychotic patients. However, the impact of age at the time of exposure has been understudied in early psychosis (EP) patients. METHOD: Two hundred and twenty-five patients aged 18-35 years were assessed at baseline and after 2, 6, 18, 24, 30 and 36 months of treatment. Patients exposed to sexual and/or physical abuse (SPA) were classified according to age at the time of first exposure (Early SPA: before age 11 years; Late SPA: between ages 12 and 15 years) and then compared to patients who were not exposed to such trauma (Non-SPA). The functional level in the premorbid phase was measured with the Premorbid Adjustment Scale (PAS) and with the Global Assessment of Functioning (GAF) scale and the Social and Occupational Functioning Assessment Scale (SOFAS) during follow-up. RESULTS: There were 24.8% of patients with a documented history of SPA. Late SPA patients were more likely to be female (p = 0.010). Comparison with non-SPA patients revealed that: (1) both Early and Late SPA groups showed poorer premorbid social functioning during early adolescence, and (2) while patients with Early SPA had poorer functional level at follow-up with lower GAF (p = 0.025) and lower SOFAS (p = 0.048) scores, Late SPA patients did not. CONCLUSION: Our results suggest a link between exposure to SPA and the later impairment of social functioning before the onset of the disease. EP patients exposed to SPA before age 12 may present long-lasting functional impairment, while patients exposed at a later age may improve in this regard and have a better functional outcome.

Presence of macronodules in thoracic sarcoidosis: prevalence and computed tomographic findings.

AIM: To assess the prevalence and radiological findings of macronodules in patients with thoracic sarcoidosis. MATERIALS AND METHODS: Data was collected regarding 226 patients with pathologically proven thoracic sarcoidosis. Among them, macronodules defined as well-defined nodules greater than 5 mm were found in 58 patients. The macronodules were evaluated by their number, size, margin, shape, lobar location, distance from the pleura, and temporal change. Patients were classified into two groups, patients with macronodules (n = 58) and without macronodules (n = 168). The level of serum angiotensin-converting enzyme (ACE), systemic involvement, and the maximum standardized uptake value (maxSUV) on (18)F-fluoro-2-deoxy-d-glucose (FDG) positron emission tomography (PET) in both groups were then compared. RESULTS: A total of 216 macronodules were identified in 58 patients. The mean number of macronodules per patient was 3.3, and the mean size was 6.3 mm. Most of the macronodules were located in lower lobes (63.4%) and showed round-to-ovoid (95.8%) shape. The mean distance from the pleura was 5 mm. In 76% of the 63 nodules that were followed using CT scanning, any interval changes in size was also accompanied by the same change in mediastinal lymphadenopathy. On comparison of the two groups, the presence of lymphadenopathy, parenchymal involvement, and the maxSUV of thoracic lymphadenopathy were shown to be statistically different. CONCLUSION: Well-defined macronodules greater than 5 mm were not uncommonly seen in patients with thoracic sarcoidosis. The macronodules are usually located in the lower lobes near the pleura, and the interval changes in mediastinal lymphadenopathy may be associated with similar changes in the size of nodules.

Gait patterns in children with limb length discrepancy.

BACKGROUND: Very few articles describe the compensations in gait caused by limb-length discrepancy (LLD). Song and colleagues explored kinematic and kinetic variables utilizing work equalization as a marker of successful compensation for LLD. They found no difference in strategies based on the location of pathology. The purpose of this study was to define the various gait patterns in patients with LLD and the impact of these compensations on gait kinetics. METHODS: Forty-three children (mean age 12.9±3.7 y) with LLD >2 cm were evaluated in the motion lab using a VICON motion system with 2 AMTI force plates. Etiologies included Legg-Calve-Perthes, developmental hip dysplasia, growth plate damage due to infection or trauma, congenital shortening of the femur or tibia, and syndromes creating shortening of the limb. Evaluation included physical examination and 3-dimensional motion data generated using the model described by Vicon Clinical Manager (VCM). For data analysis, 3 representative trials were processed with the Plug-in Gait lower-body model using the "VCM spline" filter. Walking strategies were identified by visual review. A kinematic threshold of 2 SD away from normal values was used for inclusion in each group. Strategies included: (1) pelvic obliquity with the short side lower (<-1.5 degrees); (2) flexion of the knee of the longer leg in stance (>5.2 degrees); (3) plantar flexion of the ankle on the shorter leg through the gait cycle (<0 degrees); and (4) early plantarflexion crossover of the shorter limb (plantarflexion crossover occurred before 35% of the gait cycle). Variables were extracted into Excel using PECS (Vicon Motion Systems). The mean of the 3 trials was used for analysis. Scanograms were used to establish lengths of the femur and the lower leg including the foot. The percentage difference for the subject (%LLD) was calculated as the leg length between the 2 sides divided by the length of the long side. The total mechanical work over the stride was the sum of the positive work and the absolute value of the negative work in all planes. Paired t tests were used to analyze the work differences between the short limb versus the long limb. Unpaired t tests were used to compare between the different groups (short tibias, short femurs, and controls). RESULTS: Distribution of single strategies for the group included: pelvis (11), equinis (5), vaulting (7), knee flexion (3); 17 subjects used multiple strategies. If the discrepancy was in the femur, patients chose a more distal compensation strategy, utilizing ankle movements, which resulted in more work at the ankle joint on the short limb compared with normal (P<0.0001). All subjects with tibia shortening showed pelvic obliquity (3 combined with knee flexion), which caused more work at the hip joint on the short limb compared with normal (P<0.01). Total mechanical work on the uninvolved limb was above normal for all groups (P<0.0001). CONCLUSIONS: Our study contradicts previous literature that found no difference in strategy on the basis of location of the shortening and also a higher number of children with pelvic obliquity than previously described. It appears that different compensation schemes are used by patients with LLD. The increase in work may have long-term implications for management. Future studies will include changes in kinematics and work, after intervention. Better understanding of postoperative changes from different surgical methods may provide more insight for preoperative planning and may lead to a more satisfactory outcome for specific patients. LEVEL OF EVIDENCE: Level II.

Open-label randomized clinical trial of standard neoadjuvant chemotherapy with paclitaxel followed by FEC versus the combination of paclitaxel and everolimus followed by FEC in women with triple receptor-negative breast cancer†.

BACKGROUND: Everolimus synergistically enhances taxane-induced cytotoxicity in breast cancer cells in vitro and in vivo in addition to demonstrating a direct antiproliferative activity. We aim to determine pharmacodynamics changes and response of adding everolimus to standard neoadjuvant chemotherapy in triple-negative breast cancer (TNBC). PATIENTS AND METHODS: Phase II study in patients with primary TNBC randomized to T-FEC (paclitaxel 80 mg/m(2) i.v. weekly for 12 weeks, followed by 5-fluorouracil 500 mg/m(2), epirubicin 100 mg/m(2), and cyclophosphamide 500 mg/m(2) every 3 weeks for four cycles) versus TR-FEC (paclitaxel 80 mg/m(2) i.v. and everolimus 30 mg PO weekly for 12 weeks, followed by FEC). Tumor samples were collected to assess molecular changes in the PI3K/AKT/mTOR pathway, at baseline, 48 h, 12 weeks, and at surgery by reverse phase protein arrays (RPPA). Clinical end points included 12-week clinical response rate (12-week RR), pathological complete response (pCR), and toxicity. RESULTS: Sixty-two patients were registered, and 50 were randomized, 27 received T-FEC, and 23 received TR-FEC. Median age was 48 (range 31-75). There was downregulation of the mTOR pathway at 48 h in the TR-FEC arm. Twelve-week RR by ultrasound were 29.6% versus 47.8%, (P = 0.075), and pCR were 25.9% versus 30.4% (P = 0.76) for T-FEC and TR-FEC, respectively. mTOR downregulation at 48 h did not correlate with 12-week RR in the TR-FEC group (P = 0.58). Main NCI grade 3/4 toxicities included anemia, neutropenia, rash/desquamation, and vomiting in both arms. There was one case of grade 3 pneumonitis in the TR-FEC arm. No grade 3/4 stomatitis occurred. CONCLUSION: The addition of everolimus to paclitaxel was well tolerated. Everolimus downregulated mTOR signaling but downregulation of mTOR at 48 h did not correlate with 12-week RR in the TR-FEC group. CLINICAL TRIAL NUMBER: NCT00499603.

Functional proteomics characterization of residual triple-negative breast cancer after standard neoadjuvant chemotherapy.

BACKGROUND: In this study, we used functional proteomics to determine the molecular characteristics of residual triple receptor-negative breast cancer (TNBC) patients after neoadjuvant systemic chemotherapy (NCT) and their relationship with patient outcomes in order to identify potential targets for therapy. PATIENTS AND METHODS: Protein was extracted from 54 residual TNBCs, and 76 proteins related to breast cancer signaling were measured by reverse phase protein arrays (RPPAs). Univariable and multivariable Cox proportional hazard models were fitted for each protein. Survival outcomes were estimated by the Kaplan-Meier product limit method. Training and cross validation were carried out. The coefficients estimated from the multivariable Cox model were used to calculate a risk score (RS) for each sample. RESULTS: Multivariable analysis using the top 25 proteins from univariable analysis at a false discovery rate (FDR) of 0.3 showed that AKT, IGFBP2, LKB1, S6 and Stathmin were predictors of recurrence-free survival (RFS). The cross-validation model was reproducible. The RS model calculated based on the multivariable analysis was -1.1086 × AKT + 0.2501 × IGFBP2 - 0.6745 × LKB1+1.0692 × S6 + 1.4086 × stathmin with a corresponding area under the curve, AUC = 0.856. The RS was an independent predictor of RFS (HR = 3.28, 95%CI = 2.07-5.20, P < 0.001). CONCLUSIONS: We found a five-protein model that independently predicted RFS risk in patients with residual TNBC disease. The PI3 K pathway may represent potential therapeutic targets in this resistant disease.

Functional proteomics characterization of residual breast cancer after neoadjuvant systemic chemotherapy.

BACKGROUND: The purpose of this study was to determine the functional proteomic characteristics of residual breast cancer and hormone receptor (HR)-positive breast cancer after neoadjuvant systemic chemotherapy, and their relationship with patient outcomes. METHODS: Reverse phase protein arrays of 76 proteins were carried out. A boosting approach in conjunction with a Cox proportional hazard model defined relapse predictors. A risk score (RS) was calculated with the sum of the coefficients from the final model. Survival outcomes and associations of the RS with relapse were estimated. An independent test set was used to validate the results. RESULTS: Test (n = 99) and validation sets (n = 79) were comparable. CoxBoost revealed a three-biomarker (CHK1pS345, Caveolin1, and RAB25) and a two-biomarker (CD31 and Cyclin E1) model that correlated with recurrence-free survival (RFS) in all residual breast cancers and in HR-positive disease, respectively. Unsupervised clustering split patients into high- and low risk of relapse groups with different 3-year RFS (P ≤ 0.001 both). RS was a substantial predictor of RFS (P = 0.0008 and 0.0083) after adjustment for other substantial characteristics. Similar results were found in validation sets. CONCLUSIONS: We found models that independently predicted RFS in all residual breast cancer and in residual HR-positive disease that may represent potential targets of therapy in this resistant disease.

[Schizophrenia: genes, environment and neurodevelopment]. / Gènes, environnement et neurodéveloppement: te cas de la schizophrénie.

Psychoses are complex diseases resulting from the interaction between genetic vulnerability factors and various environmental risk factors during the brain development and leading to the emergence of the clinical phenotype at the end of adolescence. Among the mechanisms involved, a redox imbalance plays an important role, inducing oxidative stress damaging to developing neurons. As a consequence, the excitatory/inhibitory balance in cortex and the pathways connecting brain areas are both impaired. Childhood and adolescence appear as critical periods of vulnerability for deleterious environmental insults. Antioxidants, applied during the environmental impacts, should allow preventing these impairments as well as their clinical consequences.