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.

Calf lengthening may improve knee recurvatum in specific children with spastic diplegic cerebral palsy.

PURPOSE: Knee hyperextension in stance is a difficult condition to treat in children with spastic diplegic cerebral palsy (CP). In children with passive knee hyperextension, the presence of contracture or spasticity of the calf leads to knee hyperextension in stance phase. We hypothesize surgical treatment of the contracture of the calf will lead to less knee hyperextension. METHODS: We performed a retrospective review of children who were evaluated in our movement laboratory over 23 years with a diagnosis of CP Gross Motor Function Classification System I, II or III. We selected children who had passive knee hyperextension on exam and who underwent calf lengthening surgery. Children were divided into two groups: early recurvatum (ER) (n = 20) and late recurvatum (LR) (n = 14). RESULTS: There was no difference in the preoperative passive knee extension among the groups or the surgeries performed. For children who had passive knee hyperextension, calf lengthening improved static dorsiflexion with knee flexion on clinical exam by 9.3° in the ER group, 9.6° in the LR group as well as dorsiflexion with knee extension on clinical exam by 9.5° in the ER group and 6.4° in the LR group. The kinematic data showed that the ER group improved their knee hyperextension by 11° (p < 0.001), whereas the LR group did not significantly change their stance phase knee position. CONCLUSION: Children with passive knee hyperextension who have a calf contracture and walk in knee hyperextension in the first half of stance phase may improve after calf lengthening.Level of Evidence: III.

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.

Use of Comprehensive Geriatric Assessment and Geriatric Screening for Older Adults in the Radiation Oncology Setting: A Systematic Review.

AIMS: Comprehensive geriatric assessment (CGA) is a multidisciplinary diagnostic process that evaluates medical, psychological, social and functional capacity. No systematic review of the use of CGA in radiation oncology has been conducted. This paper reviews the use of CGA in radiation oncology, examines whether such assessments are feasible and evaluates the effectiveness of these assessments in predicting and modifying outcomes. MATERIALS AND METHODS: We searched Medline, EMBASE, PsycINFO, CINAHL and the Cochrane Library for articles published between 1 January 1996 and 24 January 2017. RESULTS: Twelve non-randomised studies were identified; four studies used a geriatric screening tool only and the eight other studies combined a screening tool with a CGA. Most studies had small samples (mean 63 participants). Two studies identified a significant (95% confidence interval 1.5-4.8 and 1.5-6.9) association between an abnormal screening and increased risk of mortality. One study showed an ability of the CGA to influence treatment decision making, whereas six papers suggested a non-significant association between the screening tool/CGA and treatment tolerance. CONCLUSION: The studies suggest the feasibility of using a screening tool to select patients for CGA. 'Vulnerability' showed a non-statistically significant association with treatment tolerance, but a significant association with mortality.

Effect of an Arm Traction Device on Image Quality and Radiation Exposure during Neck CT: A Prospective Study.

BACKGROUND AND PURPOSE: The image quality of neck CT is frequently disturbed by streak artifact from the shoulder girdles. Our aim was to determine the effects of an arm traction device on image quality and radiation exposure in neck CT. MATERIALS AND METHODS: Patients with lymphoma with complete remission who were scheduled to undergo 2 consecutive follow-up neck CT scans for surveillance within a 1-year interval were enrolled in this prospective study. They underwent 2 consecutive neck CT scans (intervention protocol: patients with an arm traction device; standard protocol: no positioning optimization) on the same CT system. The primary outcome measures were image noise in the lower neck and dose-length product. Secondary outcomes were streak artifacts in the supraclavicular fossa, volume CT dose index, and the extent of the biacromial line shift. RESULTS: Seventy-three patients were enrolled and underwent 2 consecutive CT scans with a mean interval of 155 days. In the intervention protocol, a mean noise reduction in the lower neck of 25.2%-28.5% (P < .001) was achieved, and a significant decrease in dose-length product (413 versus 397, P < .001) was observed. The intervention protocol significantly decreased streak artifacts (P < .001) and volume CT dose index (13.9 versus 13.4, P < .001) and could lower the biacromial line an average of 2.1 cm. CONCLUSIONS: An arm traction device can improve image quality and reduce radiation exposure during neck CT. The device can be simply applied in cooperative patients with suspected lower neck lesions, and the approach offers distinct advantages over the conventional imaging protocol.

Implication of the glutamate-cystine antiporter xCT in schizophrenia cases linked to impaired GSH synthesis.

xCT is the specific chain of the cystine/glutamate antiporter, which is widely reported to support anti-oxidant defenses in vivo. xCT is therefore at the crossroads between two processes that are involved in schizophrenia: oxidative stress and glutamatergic neurotransmission. But data from human studies implicating xCT in the illness and clarifying the upstream mechanisms of xCT imbalance are still scarce. Low glutathione (GSH) levels and genetic risk in GCLC (Glutamate-Cysteine Ligase Catalytic subunit), the gene of limiting synthesizing enzyme for GSH, are both associated with schizophrenia. In the present study, we aimed at determining if xCT regulation by the redox system is involved in schizophrenia pathophysiology. We assessed whether modulating GCLC expression impact on xCT expression and activity (i) in fibroblasts from patients and controls with different GCLC genotypes which are known to affect GCLC regulation and GSH levels; (ii) in rat brain glial cells, i.e., astrocytes and oligodendrocytes, with a knock-down of GCLC. Our results highlight that decreased GCLC expression leads to an upregulation of xCT levels in patients' fibroblasts as well as in astrocytes. These results support the implication of xCT dysregulation in illness pathophysiology and further indicate that it can result from redox changes. Additionally, we showed that these anomalies may already take place at early stages of psychosis and be more prominent in a subgroup of patients with GCLC high-risk genotypes. These data add to the existing evidence identifying the inflammatory/redox systems as important targets to treat schizophrenia already at early stages. SCHIZOPHRENIA: ANTIOXIDANT DEFICIT INCREASES A KEY NEUROTRANSMITTER TRANSPORTER: Deficit of antioxidant synthesis in schizophrenia leads to oxidative stress and changes in neurotransmitter transporter. Led by Kim Do, a team of researchers from Lausanne University in Switzerland investigated the role of the cell-surface transport protein xCT in schizophrenia. They found that an enzyme responsible for antioxidant production is disturbed in patients. This leads to decreased antioxidant levels and consequently to oxidative stress-i.e. the accumulation of reactive oxygen molecules, damaging the cells component and impairing cell functioning-which in turn affects the functioning of the antioxidant pathway, including xCT. xCT, which exports the neurotransmitter glutamate, is thus overproduced in schizophrenia. The resulting increase of neurotransmitter activity, alongside the increase in oxidative stress, is thought to play a major role in the pathophysiology of schizophrenia, including at early stages of the disease.

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.

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.

ATM function and its relationship with ATM gene mutations in chronic lymphocytic leukemia with the recurrent deletion (11q22.3-23.2).

Approximately 10-20% of chronic lymphocytic leukemia (CLL) patients exhibit del(11q22-23) before treatment, this cohort increases to over 40% upon progression following chemoimmunotherapy. The coding sequence of the DNA damage response gene, ataxia-telangiectasia-mutated (ATM), is contained in this deletion. The residual ATM allele is frequently mutated, suggesting a relationship between gene function and clinical response. To investigate this possibility, we sought to develop and validate an assay for the function of ATM protein in these patients. SMC1 (structural maintenance of chromosomes 1) and KAP1 (KRAB-associated protein 1) were found to be unique substrates of ATM kinase by immunoblot detection following ionizing radiation. Using a pool of eight fluorescence in situ hybridization-negative CLL samples as a standard, the phosphorylation of SMC1 and KAP1 from 46 del (11q22-23) samples was analyzed using normal mixture model-based clustering. This identified 13 samples (28%) that were deficient in ATM function. Targeted sequencing of the ATM gene of these samples, with reference to genomic DNA, revealed 12 somatic mutations and 15 germline mutations in these samples. No strong correlation was observed between ATM mutation and function. Therefore, mutation status may not be taken as an indicator of ATM function. Rather, a direct assay of the kinase activity should be used in the development of therapies.

Impaired fornix-hippocampus integrity is linked to peripheral glutathione peroxidase in early psychosis.

Several lines of evidence implicate the fornix-hippocampus circuit in schizophrenia. In early-phase psychosis, this circuit has not been extensively investigated and the underlying mechanisms affecting the circuit are unknown. The hippocampus and fornix are vulnerable to oxidative stress at peripuberty in a glutathione (GSH)-deficient animal model. The purposes of the current study were to assess the integrity of the fornix-hippocampus circuit in early-psychosis patients (EP), and to study its relationship with peripheral redox markers. Diffusion spectrum imaging and T1-weighted magnetic resonance imaging (MRI) were used to assess the fornix and hippocampus in 42 EP patients compared with 42 gender- and age-matched healthy controls. Generalized fractional anisotropy (gFA) and volumetric properties were used to measure fornix and hippocampal integrity, respectively. Correlation analysis was used to quantify the relationship of gFA in the fornix and hippocampal volume, with blood GSH levels and glutathione peroxidase (GPx) activity. Patients compared with controls exhibited lower gFA in the fornix as well as smaller volume in the hippocampus. In EP, but not in controls, smaller hippocampal volume was associated with high GPx activity. Disruption of the fornix-hippocampus circuit is already present in the early stages of psychosis. Higher blood GPx activity is associated with smaller hippocampal volume, which may support a role of oxidative stress in disease mechanisms.

Current status of medical radiation exposure in Korea - recent efforts to develop a radiation exposure control system focussed on justification and optimisation.

Radiation exposure from diagnostic medical imaging has increased in Korea. Radiological societies play a key role in radiation safety issues in Korea, including guidelines, accreditation, advocacy, scientific activity, and education. Any medical radiation exposure must be justified, and examinations using ionising radiation must be optimised. Education of referring physicians and radiologists is also important for justification. Medical physicists and radiographers have an important role to play in quality management and optimisation. Regulations are essential to control medical radiation exposure. Therefore, national organisations have made a significant effort to regulate and monitor medical radiation exposure using guidelines, accreditation, and even the law. Medical radiation exposure must be controlled, and this could be achieved by continuous interest from health professionals and organisations.

Outcomes for patients with chronic lymphocytic leukemia and acute leukemia or myelodysplastic syndrome.

Acute leukemia (AL) and myelodysplastic syndrome (MDS) are uncommon in chronic lymphocytic leukemia (CLL). We retrospectively identified 95 patients with CLL, also diagnosed with AL (n=38) or MDS (n=57), either concurrently (n=5) or subsequent (n=90) to CLL diagnosis and report their outcomes. Median number of CLL treatments prior to AL and MDS was 2 (0-9) and 1 (0-8), respectively; the most common regimen was purine analog combined with alkylating agent±CD20 monoclonal antibody. Twelve cases had no prior CLL treatment. Among 38 cases with AL, 33 had acute myelogenous leukemia (AML), 3 had acute lymphoid leukemia (ALL; 1 Philadelphia chromosome positive), 1 had biphenotypic and 1 had extramedullary (bladder) AML. Unfavorable AML karyotype was noted in 26, and intermediate risk in 7 patients. There was no association between survival from AL and number of prior CLL regimens or karyotype. Expression of CD7 on blasts was associated with shorter survival. Among MDS cases, all International Prognostic Scoring System (IPSS) were represented; karyotype was unfavorable in 36, intermediate in 6 and favorable in 12 patients; 10 experienced transformation to AML. Shorter survival from MDS correlated with higher risk IPSS, poor-risk karyotype and increased number of prior CLL treatments. Overall, outcomes for patients with CLL subsequently diagnosed with AL or MDS were very poor; AL/MDS occurred without prior CLL treatment. Effective therapies for these patients are desperately needed.

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.

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.

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.

Comparison of hamstring transfer with hamstring lengthening in ambulatory children with cerebral palsy: further follow-up.

BACKGROUND: Overactivity or contractures of the hamstring muscles in ambulatory children with cerebral palsy (CP) can lead to either a jump gait (knee flexion associated with ankle plantar flexion) or a crouch gait (knee flexion associated with ankle dorsiflexion). Hamstring lengthening is performed to decrease stance knee flexion. However, this procedure carries the potential risk of weakening hip extension power as well as recurrence over time; therefore, surgeons have adopted a modified procedure wherein the semitendinosus and gracilis are transferred above the knee joint, along with lengthening of the semimembranosus and biceps femoris. PURPOSE: The purpose of our study is to evaluate the differences between hamstring lengthening alone (HSL group) and hamstring lengthening plus transfer (HST group) in the treatment of flexed knee gait in ambulatory children with CP. We hypothesized that recurrence of increased knee flexion in the stance phase will be less in the HST group at long-term follow-up, and hip extensor power will be better preserved. METHODS: Fifty children with CP who underwent hamstring surgery for flexed knee gait were retrospectively reviewed. All subjects underwent a pre-operative gait study, a follow-up post-operative gait study, and a long-term gait study. The subjects were divided into two groups; HSL group (18 subjects) or HST group (32 subjects). The mean age at surgery was 9.9 ± 3.3 years. The mean follow-up time was 4.4 ± 0.9 (2.7-6.3) years. RESULTS: On physical examination, both groups showed improvement in straight leg raise, knee extension, popliteal angle, and maximum knee extension in stance at the first post-op study, and maintained this improvement at the long-term follow-up, with the exception of straight leg raise, which slightly worsened in both groups at the final follow-up. Both groups improved maximum knee extension in stance at the initial follow-up, and maintained this at the long-term follow-up. Only the HST group showed significant (p < 0.05) improvement in the peak hip extension power in stance at the first post-op study, and this increased further at the final follow-up. In the HSL group, there was an initial slight decrease in the hip extension power, which subsequently increased to pre-operative values at the long-term study. Only the HST group showed increase of the average anterior pelvic tilt at the long-term follow-up study, although this was small in magnitude. There were two subjects who developed knee recurvatum at the post-op study, and both were in the HST group. CONCLUSIONS: There is no clear benefit in regards to recurrence when comparing HST to HSL in the long term. In both HSL and HST, there was reduction of stance phase knee flexion in the long term, with no clear advantage in either group. Longer follow-up is needed for additional recurrence information. There was greater improvement of hip extension power in the HST group, which may justify the additional operative time of the transfer. SIGNIFICANCE: This study helps pediatric orthopedic surgeons choose between two different techniques to treat flexed knee gait in patients with CP by showing the long-term outcome of both procedures.

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.