Airway Reactance Predicts Static Lung Hyperinflation in Severe Asthma

Background: Static lung hyperinflation (SLH) measured using body plethysmography in patients with asthma is associated with poor outcomes. The severity of SLH may be associated with small airway dysfunction (SAD), which can be measured using impulse oscillometry (IOS). Objective: This study aims to determine the correlation between SLH and SAD in patients with severe asthma and assess the improvement in SLH and SAD with treatment. Methods: We analyzed data from patients who were enrolled in the Taiwan Severe Asthma Registry, which comprises a prospective observational cohort. Plethysmography and IOS were performed regularly. The relationship between spirometry and IOS parameters was determined. Changes in the clinical outcomes in response to treatment were analyzed. Results: Of 107 patients with severe asthma, 83 (77.6%) had SLH based on an increased residual volume to total lung capacity ratio (RV/TLC). Most patients were older women with worse pulmonary function and SAD than those without SLH. SAD, defined as increased airway resistance/reactance, was significantly correlated with SLH. Airway reactance at 5 Hz (X5) ≤−0.21 kPa/(L/s) detected SLH with an area under the receiver operating characteristic curve of 0.84 (P<.0001; sensitivity, 85.2%; and specificity, 83.3%). After 12 months, patients who received add-on biologics (vs those who did not) had significantly reduced exacerbations, fractional exhaled nitric oxide level, and blood eosinophil counts, as well as improved forced expiratory volume in the first second, X5, and a trend toward reduced RV/TLC ratio. Conclusion: In severe asthma, airway reactance (X5) could be a novel parameter for assessing SLH. (AU)

Antecedentes: En el asma bronquial, la hiperinsuflación pulmonar estática (SLH) medida mediante pletismografía corporal (Pleth) se asocia a un peor pronóstico. La gravedad de la SLH podría estar asociada con la disfunción de las vías respiratorias pequeñas (SAD), que puede medirse mediante la oscilometría de impulsos (IOS). Objetivo: Este estudio pretende determinar la correlación entre el SLH y la SAD en pacientes con asma grave, y la mejora de ambos parámetros en respuesta al tratamiento. Métodos: Se analizaron los datos de los pacientes que se inscribieron en el Registro de Asma Grave de Taiwán, una cohorte observacional prospectiva. Se realizaron periódicamente mediciones de Pleth e IOS. Se determinó la relación entre los parámetros espirométricos e IOS. Se analizaron los cambios en los parámetros clínicos y funcionales en respuesta al tratamiento. Resultados: De una muestra de 107 pacientes con asma grave, 83 (77,6%) presentaban SLH, definida mediante una relación volumen residual/capacidad pulmonar total (VR/CTP) aumentada. La mayoría de los pacientes eran mujeres de edad avanzada con peor función pulmonar y SAD, en comparación con los que no tenían SLH. El SAD por aumento de la resistencia/reactancia de las vías respiratorias se correlacionó significativamente con el SLH. La reactancia de las vías respiratorias a 5 Hz (X5) ≤-0,21 [kPa/(L/s)] detectó el SLH con un área bajo la curva ROC de 0,84 (p < 0,0001, sensibilidad = 85,2% y especificidad = 83,3%). Después de 12 meses, los pacientes que recibieron tratamiento biológico adicional presentaron una reducción significativa de las exacerbaciones, del nivel de óxido nítrico exhalado, del recuento de eosinófilos en sangre, una mejora del volumen espiratorio forzado en el primer segundo, de la X5, y una tendencia a la reducción del cociente RV/TLC en comparación con los que no recibieron tratamiento biológico... (AU)

Airway Reactance Predicts Static Lung Hyperinflation in Severe Asthma.

BACKGROUND AND OBJECTIVES: Background: Static lung hyperinflation (SLH) measured using body plethysmography in patients with asthma is associated with poor outcomes. The severity of SLH may be associated with small airway dysfunction (SAD), which can be measured using impulse oscillometry (IOS). Objective: This study aims to determine the correlation between SLH and SAD in patients with severe asthma and assess the improvement in SLH and SAD with treatment. METHODS: We analyzed data from patients who were enrolled in the Taiwan Severe Asthma Registry, which comprises a prospective observational cohort. Plethysmography and IOS were performed regularly. The relationship between spirometry and IOS parameters was determined. Changes in the clinical outcomes in response to treatment were analyzed. RESULTS: Of 107 patients with severe asthma, 83 (77.6%) had SLH based on an increased residual volume to total lung capacity ratio (RV/ TLC). Most patients were older women with worse pulmonary function and SAD than those without SLH. SAD, defined as increased airway resistance/reactance, was significantly correlated with SLH. Airway reactance at 5 Hz (X5) ≤-0.21 kPa/(L/s) detected SLH with an area under the receiver operating characteristic curve of 0.84 (P<.0001; sensitivity, 85.2%; and specificity, 83.3%). After 12 months, patients who received add-on biologics (vs those who did not) had significantly reduced exacerbations, fractional exhaled nitric oxide level, and blood eosinophil counts, as well as improved forced expiratory volume in the first second, X5, and a trend toward reduced RV/TLC ratio. CONCLUSIONS: In severe asthma, airway reactance (X5) could be a novel parameter for assessing SLH.

MAGI1-IT1 stimulates proliferation in non-small cell lung cancer by upregulating AKT1 as a ceRNA.

OBJECTIVE: This study aims to illustrate the potential role of MAGI1-IT1 in the progression of non-small cell lung cancer (NSCLC) and the underlying mechanism. PATIENTS AND METHODS: The relative level of MAGI1-IT1 in normal lung tissues and NSCLC tissues was determined. Its level in NSCLC patients with different tumor sizes (<5 cm or >5 cm), metastatic statues (positive or negative), and tumor staging (stage I+II or stage III+IV) was detected as well. The prognostic potential of MAGI1-IT1 in evaluating the overall survival (OS) and progression-free survival (PFS) of NSCLC patients was assessed by the Kaplan-Meier method. In A549 and PC-9 cells, the regulatory effect of MAGI1-IT1 on the proliferative ability was examined by the cell counting kit-8 (CCK-8), colony formation, and 5-Ethynyl-2'-deoxyuridine (EdU) assay. The target miRNA of MAGI1-IT1 and the target gene binding to miRNA-512-3p were predicted using the Diana database. The interactions among MAGI1-IT1/miRNA-512-3p/AKT1 regulatory loop were tested by the Dual-luciferase reporter gene assay and RNA immunoprecipitation (RIP) assay. At last, the rescue experiments were carried out to uncover the regulatory effect of MAGI1-IT1/AKT1 axis on NSCLC progression. RESULTS: MAGI1-IT1 was upregulated in NSCLC tissues. Its level was higher in NSCLC patients with larger tumor size, positive metastasis, or advanced stage. High level of MAGI1-IT1 predicted worse OS and PFS in NSCLC patients. The knockdown of MAGI1-IT1 remarkably attenuated the proliferative ability in A549 and PC-9 cells. MAGI1-IT1 could target miRNA-512-3p, and AKT1 was the target gene of miR-512-3p. The overexpression of AKT1 stimulated lung cancer cells to proliferate. Of note, the elevated proliferative rate in lung cancer cells overexpressing AKT1 was reversed by the silence of MAGI1-IT1. CONCLUSIONS: MAGI1-IT1 is upregulated in NSCLC tissues and cell lines, and predicts a poor prognosis in NSCLC patients. MAGI1-IT1 stimulates proliferative ability in NSCLC by upregulating the AKT1 level by binding to miRNA-512-3p.

[Brain derived neurotrophic factor enhances the role of mesenchymal stem cells in inhibiting follicular helper T cells].

Objective: To investigate the effect of brain derived neurotrophic factor (BDNF) on mesenchymal stem cells (MSC) inhibiting follicular helper T cells (Tfh cells). Methods: The contents of indoleamine 2,3-dioxygenase (IDO), IL-10, TGF-ß and IL-21 in MSC culture supernatant were detected by ELISA; The peripheral blood of healthy volunteers were collected, and lymphocyte in peripheral blood was separated by human lymphocyte separation solution; Co-cultures of MSC and lymphocyte were performed by Transwell chamber, and the proportion of CD4(+)CXCR5(+) Tfh cells and their subtypes were detected by flow cytometry. Results: ①The concentrations of IL-10, TGF-ß, and IDO in the supernatant of BDNF group (BDNF-stimulated MSC) were higher than those of the control ones (adding PBS with the same volume) [IL-10: (42.1±4.4) ng/ml vs (19.3±2.1) ng/ml, t=4.761, P=0.009; TGF-ß: (13.9±1.7) ng/ml vs (5.3±0.6) ng/ml, t=5.129, P=0.008; IDO: (441.3±56.9) ng/ml vs (226.7±37.6) ng/ml, t=3.130, P=0.035]; ②The comparisons between BDNF (co-culture of lymphocyte and BDNF-stimulated MSC) and MSC groups (co-culture of lymphocyte and MSC) were detailed as of follows: the proportion of CD4(+) CXCR5(+)Tfh cells were lower [(3.37±0.21)% vs (6.51±0.27)%, t=9.353, P<0.001], the proportion of CD4(+) CXCR5(+)CXCR3(+) CCR6(-) Tfh cells were higher [(41.14±2.04)% vs (26.72±2.57)%, t=4.383, P=0.012], CD4(+)CXCR5(+)CXCR3(-)CCR6(-) Tfh2 cells and CD4(+)CXCR5(+)CXCR3(-)CCR6(+) Tfh17 cells were lower [Tfh2: (30.16±5.38)% vs (43.26±4.11)%, t=4.426, P=0.012; Tfh17: (15.61±1.52)% vs (22.32±0.72)%, t=4.202, P=0.014], the proportion of CD4(+)CXCR5(+)Foxp3(+) Tfr cells were higher [(4.95±0.22)% vs (2.32±0.16)%, t=10.241, P<0.001], the concentration of IL-21 in the lymphocyte supernatant was lower [(0.28±0.03) ng/ml vs (0.85±0.08) ng/ml, t=6.675, P=0.003]. Conclusion: BDNF could enhance the inhibitory effect of MSC on Tfh cells through inhibiting the increasing of Tfh cells and the differentiations of Tfh2 and Tfh17 cells.

[Ventilator-associated pneumonia among premature infants <34 weeks' gestational age in neonatal intensive care unit in China: a multicenter study].

Objective: To investigate the incidence and pathogen distribution of ventilator-associated pneumonia (VAP) among preterm infants admitted to level Ⅲ neonatal intensive care units (NICU) in China. Method: A prospective study was conducted in 25 level Ⅲ NICU, enrolling all preterm infants <34 weeks gestational age admitted to the participating NICU within the first 7 days of life from May 2015 to April 2016. Chi-square test, t test and Mann-Whitney U test were used for statistical analysis. Result: A total of 7 918 patients were enrolled, within whom 4 623(58.4%) were males. The birth weight was (1 639±415) g and the gestational age was (31.4±2.0) weeks; 4 654(58.8%) infants required non-invasive mechanical ventilation and 2 154(27.2%) required intubation. Of all the mechanically ventilated patients, VAP occurred in 95 patients. The overall VAP rate was 7.0 episodes per 1 000 ventilator days, varying from 0 to 34.4 episodes per 1 000 ventilator days in different centers. The incidence of VAP was 9.6 and 6.0 per 1 000 ventilator days in children's hospitals and maternity-infant hospitals respectively, without significant differences (t=1.002, P=0.327). Gram-negative bacilli (76 strains, 91.6%) were the primary VAP microorganisms, mainly Acinetobacter baumannii (24 strains, 28.9%), Klebsiella pneumonia (23 strains, 27.7%), and Pseudomonas aeruginosa (10 strains, 12.0%). Conclusion: The incidence of VAP in China is similar to that in developed counties, with substantial variability in different NICU settings. More efforts are needed to monitor and evaluate the preventable factors associated with VAP and conduct interventions that could effectively reduce the occurrence of VAP.

Immunohistochemical studies and fluorodeoxyglucose uptake on positron emission tomography in pharyngeal cancer for predicting radiotherapy-based treatment outcomes.

OBJECTIVES: This study correlated immunohistochemical studies with fluorodeoxyglucose (FDG) uptake on positron emission tomography-computed tomography (PET-CT) and identified prognostic factors for radiotherapy (RT)-based treatment outcomes in patients with squamous cell carcinoma of the oropharynx and hypopharynx. METHODS: Genomic data from pre-treatment biopsy specimens (Glut1, CAIX, VEGF, HIF-1α, EGFR, Ki-67, Bcl-2, CLAUDIN-4, YAP-1, c-Met and p16) of 76 patients were analysed using tissue microarrays. FDG uptake was evaluated using the maximum standardised uptake value (SUVmax), metabolic tumour volume (MTV) and total lesion glycolysis (TLG). RESULTS: The overexpression of Glut1 positively associated with increased values of the SUVmax, MTV and TLG, whereas VEGF and HIF-1α expression with the MTV and TLG, respectively. A VEGF immunoreactive score (IRS) >2 (P = 0.001, hazard ratio [HR] = 3.94) and an MTV defined by an SUV of 2.5 (MTV2.5) >14.5 mL (P = 0.004, HR = 3.31) were prognostic factors for low cause-specific survival, whereas a VEGF IRS >2 (P = 0.02, HR = 2.83) for low primary relapse-free survival. CONCLUSION: The overexpression of Glut1, VEGF and HIF-1α associated with increased FDG uptake. For patients with pharyngeal cancer requiring RT, the treatment outcome can be stratified by VEGF and MTV2.5.

Gambogic acid synergistically potentiates cisplatin-induced apoptosis in non-small-cell lung cancer through suppressing NF-κB and MAPK/HO-1 signalling.

BACKGROUND: Gambogic acid (GA) has been reported to have potent anticancer activity and is authorised to be tested in phase II clinical trials for treatment of non-small-cell lung cancer (NSCLC). The present study aims to investigate whether GA would be synergistic with cisplatin (CDDP) against the NSCLC. METHODS: 1-(4,5-Dimethylthiazol-2-yl)-3,5-diphenylformazan (MTT), combination index (CI) isobologram, western blot, quantitative PCR, flow cytometry, electrophoretic mobility shift assay, xenograft tumour models and terminal deoxynucleotide transferase-mediated dUTP nick-end labelling analysis were used in this study. RESULTS: The cell viability results showed that sequential CDDP-GA treatment resulted in a strong synergistic action in A549, NCI-H460, and NCI-H1299 cell lines, whereas the reverse sequence and simultaneous treatments led to a slight synergistic or additive action. Increased sub-G1 phase cells and enhanced PARP cleavage demonstrated that the sequence of CDDP-GA treatment markedly increased apoptosis in comparison with other treatments. Furthermore, the sequential combination could enhance the activation of caspase-3, -8, and 9, increase the expression of Fas and Bax, and decrease the expression of Bcl-2, survivin and X-inhibitor of apoptosis protein (X-IAP) in A549 and NCI-H460 cell lines. In addition, increased apoptosis was correlated with enhanced reactive oxygen species generation. Importantly, it was found that, followed by CDDP treatment, GA could inhibit NF-κB and mitogen-activated protein kinase (MAPK)/heme oxygenase-1 (HO-1) signalling pathways, which have been validated to reduce ROS release and confer CDDP resistance. The roles of NF-κB and MAPK pathways were further confirmed by using specific inhibitors, which significantly increased ROS release and apoptosis induced by the sequential combination of CDDP and GA. Moreover, our results indicated that the combination of CDDP and GA exerted increased antitumour effects on A549 xenograft models through inhibiting NF-κB, HO-1, and subsequently inducing apoptosis. CONCLUSION: Gambogic acid sensitises lung cancer cells to CDDP in vitro and in vivo in NSCLC through inactivation of NF-κB and MAPK/HO-1 signalling pathways, providing a rationale for the combined use of CDDP and GA in lung cancer chemotherapy.

Phthalates suppress type I interferon in human plasmacytoid dendritic cells via epigenetic regulation.

BACKGROUND: Exposure to environmental endocrine-disrupting chemicals (EDCs) is associated with allergy, chronic inflammation, and immunodeficiency. Phthalates, the common EDCs used in plastic industry, may act as adjuvants to disrupt immune system and enhance allergy. Plasmacytoid DCs (pDCs) are predominant cells secreting type I interferon (IFN) against infection and are professional antigen-presenting cells in regulating adaptive immunity. However, the effects of phthalates on the function of pDCs are unknown. METHODS: Circulating pDCs were isolated from healthy subjects, were pretreated with diethylhexyl phthalate (DEHP) and butyl benzyl phthalate (BBP), and were stimulated with Toll-like receptor (TLR)-9 agonist CpG. IFN-α/IFN-ß levels, surface markers, and T-cell stimulatory function were investigated using ELISA, flow cytometry, and pDC/T-cell coculture assay. Mechanisms were investigated using receptor antagonists, pathway inhibitors, Western blotting, and chromatin immunoprecipitation. RESULTS: Diethylhexyl phthalate and butyl benzyl phthalate suppressed CpG-induced IFN-α/IFN-ß expression in pDCs, and the effect was reversed by aryl hydrocarbon receptor (AHR) antagonist. Diethylhexyl phthalate suppressed CpG-activated mitogen-activated protein kinase (MAPK)-MEK1/2-ERK-ELK1 and NFκB signaling pathways. Diethylhexyl phthalate suppressed CpG-induced interferon regulatory factor (IRF)-7 expression by suppressing histone H3K4 trimethylation at IRF7 gene promoter region through inhibiting translocation of H3K4-specific trimethyltransferase WDR5 from cytoplasm into nucleus. Butyl benzyl phthalate or diethylhexyl phthalate-treated pDCs suppressed IFN-γ but enhanced IL-13 production by CD4+ T cells. CONCLUSION: Phthalates may interfere with immunity against infection and promote the deviation of Th2 response to increase allergy by acting on human pDCs via suppressing IFN-α/IFN-ß expression and modulating the ability to stimulate T-cell responses.

High case volume of radiation oncologists is associated with better survival of nasopharyngeal carcinoma patients treated with radiotherapy: a multifactorial cohort analysis.

OBJECTIVES: The relationship between physician case volume and patient outcome in patients with head and neck cancers such as nasopharyngeal carcinoma treated by radiotherapy is unknown. This study was designed to investigate the association between the case volume of radiation oncologists and the survival of patients with nasopharyngeal carcinoma. DESIGN: Retrospective cohort study. SETTING: Based on nationwide claims data (National Health Research Insurance Database) in the years 2002-2008. PARTICIPANTS: Newly diagnosed patients with nasopharyngeal carcinoma receiving curative radiotherapy in the year 2003. MAIN OUTCOME MEASURES: Overall survival until 2008. We used the running log-rank test to decide the optimal threshold for categorising the case volume of radiation oncologists. The characteristics of patients, their treatments and contact with health service providers were considered as co-explanatory variables. The log-rank test and Cox regression were performed. Sensitivity analyses were carried out regarding major study assumptions. RESULTS: Five hundred and sixty-two patients with nasopharyngeal carcinoma newly diagnosed in 2003 were identified as the study cohort. The 5-year overall survival was better among patients treated by high-volume (≥6 patients in year 2002) radiation oncologists than by low-volume (<6 patients in year 2002) radiation oncologists (77%versus 64%, P = 0.0007). The adjusted hazard ratio of death was 0.65 (95% confidence interval, 0.48-0.91) upon multivariate analysis. Patients aged at least 65 years also had a lower survival rate than those younger than 65 years old (adjusted hazard ratio of death: 2.81, 95% confidence interval: 1.94-4.08).The physician case volume and patient outcome effect remained the same after sensitivity analyses. CONCLUSIONS: Patients with nasopharyngeal carcinoma treated by high-volume radiation oncologists have better survival compared with those treated by low-volume radiation oncologists. Further studies are needed to verify our findings with similar cancer cohorts treated by modern radiotherapy techniques or other types of radiotherapy.

Flexible interpretation of a decision rule by supplementary eye field neurons.

Since the environment is in constant flux, decision-making capabilities of the brain must be rapid and flexible. Yet in sensory motion processing pathways of the primate brain where decision making has been extensively studied, the flexibility of neurons is limited by inherent selectivity to motion direction and speed. The supplementary eye field (SEF), an area involved in decision making on moving stimuli, is not strictly a sensory or motor structure, and hence may not suffer such limitations. Here we test whether neurons in the SEF can flexibly interpret the rule of a go/nogo task when the decision boundary in the task changes with each trial. The task rule specified that the animal pursue a moving target with its eyes if and when the target entered a visible zone. The size of the zone was changed from trial to trial in order to shift the decision boundary, and thereby assign different go/nogo significance to the same motion trajectories. Individual SEF neurons interpreted the rule appropriately, signaling go or nogo in compliance with the rule and not the direction of motion. The results provide the first evidence that individual neurons in frontal cortex can flexibly interpret a rule that governs the decision to act.

Randomized, double-blind, placebo-controlled trial of hydroxyurea in spinal muscular atrophy.

OBJECTIVE: The purpose of this study was to evaluate the safety and efficacy of hydroxyurea (HU) in spinal muscular atrophy (SMA) in a randomized, double-blind, placebo-controlled trial. METHODS: Twenty-eight patients with type 2 SMA and 29 patients with type 3 SMA were randomly assigned (2:1) to receive HU or matching placebo for 18 months. HU was initiated at 10 mg/kg/day with an 8-week titration to 20 mg/kg/day. Subjects were assessed at baseline (T0) and monthly for the first 2 months (T1-T2) and then every 2 months throughout treatment (T3-T10) and posttreatment periods (T11-T13). The primary outcome measures were the Gross Motor Function Measure (GMFM), Manual Muscle Test (MMT), and serum full-length survivor motor neuron (flSMN) mRNA. The secondary outcome measures were Modified Hammersmith Functional Motor Scale and forced vital capacity (FVC). RESULTS: Fifty-five patients completed this trial, which lasted from March 2007 to June 2009. Except for neutropenia, we found no differences in adverse events between the 2 groups. Compared with the placebo group, the HU group had -1.88 for GMFM (p = 0.11), -0.55 for MMT (p = 0.49), and 2.17 for flSMN mRNA (p = 0.13). Similarly, we found no difference in mean improvement of the secondary endpoints. Both groups had a trend toward a decline in FVC with little change in strength and motor function. CONCLUSION: Under the current regimen and schedule, HU brought about no improvement in patients with type 2 and 3 SMA, and its main side effect was neutropenia. CLASSIFICATION OF EVIDENCE: This trial provides Class I evidence that HU 20 mg/kg/day does not effectively treat SMA.

Late toxicities in concurrent chemoradiotherapy using high-dose-rate intracavitary brachytherapy plus weekly cisplatin for locally advanced cervical cancer: a historical cohort comparison against two previous different treatment schemes.

PURPOSE: To determine the long-term toxicity of concurrent chemoradiotherapy (CCRT), using high-dose rate intracavitary brachytherapy (HDRICB) compared to radiation (RT) alone in patients with advanced cervical cancer using a control-cohort study. METHODS: A total of 332 cases of Stage IIB-III disease were included in this comparative study. Seventy-three patients were treated with a 3-insertion schedule and labeled group A, whereas the other 146 patients with a 4-insertion schedule became group B. One hundred and thirteen patients treated by a 4-insertion protocol with concurrent weekly cisplatin were labeled group C. RESULTS: The cumulative rate of grade 2 or above rectal complication was 13.7% for group A, 9.6% for the group B and 15.9% for group C (p = 0.76), whereas the grade 3 to 4 non-rectal radiation-induced intestinal injury was 6.8% for group A, 6.2% for group B and 9.7% for group C (p = 0.20). Grade 2 to 4 late bladder toxicity was higher in group C, with the cumulative rate being 5.5% for group A, 4.8% for group B and 15.0% for group C (p = 0.004). The independent factor for a rectal complication was the occurrence of a bladder complication (p = 0.01, hazard ratio 3.06). The independent factors for bladder complications were the use of CCRT (p = 0.01, hazard ratio 2.08), and the occurrence of rectal complications (p = 0.02, hazard ratio 2.77). CONCLUSIONS: When treating advanced cervical cancer, HDRICB consisting of four 6 Gy insertions and weekly cisplatin shows a trend of increasing late bladder complications. The interval between drug administration and HDRICB should be kept long enough to avoid any synergistic effect of both regimens.

The outcome and prognostic factors in patients with aspiration pneumonia during concurrent chemoradiotherapy for head and neck cancer.

This study aimed to investigate the outcome in patients with aspiration pneumonia during definitive concurrent chemoradiotherapy for head and neck cancer. The data of 595 patients with head and neck cancer treated by chemoradiotherapy were reviewed. Forty-one patients were identified as developing symptomatic aspiration pneumonia during treatment and were analysed for this study. The definition of symptomatic aspiration pneumonia fit three criteria: (1) at least one event of aspiration during the treatment or evidence of grade 2 or above dysphagia during treatment; (2) clinical or radiographic signs of pneumonia or pneumonitis; and (3) no evidence of grade 4 haematological toxicity before the outbreak of pneumonia. Termination of allocated radiotherapy was noted in 10 patients. A treatment break was observed in 26 patients, whereas irradiation was prolonged more than 1 week in 11 patients. Logistic regression analysis showed the dysphagia score during the treatment course and the chest roentgenography pattern following symptomatic aspiration pneumonia were found to independently influence the outcome. Aspiration pneumonia occurring during chemoradiotherapy for head and neck cancer has a detrimental effect on the treatment outcome. Intensive medical care is essential for this group of patients with a dysphagia score of 3 during treatment and an unfavourable chest film pattern.

Prenatal morphine alters the synaptic complex of postsynaptic density 95 with N-methyl-D-aspartate receptor subunit in hippocampal CA1 subregion of rat offspring leading to long-term cognitive deficits.

Infants who are passively exposed to morphine or heroin through their addicted mothers usually develop neurobiological changes. The postsynaptic density 95 (PSD-95) protein, a submembranous cytoskeletal specialization, is dynamically linked with N-methyl-d-aspartate receptors (NMDARs) to form a synaptic complex in postsynaptic neurons. This complex serves important neurobiological functions, including mammalian learning and memory. However, the effects of prenatal morphine exposure on this synaptic complex are not well understood. In this study, we determined whether prenatal morphine exposure altered the synaptic complex association between PSD-95 and three major NMDAR subunits (NR1, NR2A, and NR2B), at the mRNA and protein levels, within the hippocampal CA1 subregion (an important integration area for mammalian learning and memory) of rat offspring along with the performance of long-term cognitive functions. Sprague-Dawley rat offspring from morphine-addicted mothers were studied at a younger age (postnatal day 14; P14) and at an older age (P45). Subsequently, an eight-arm radial maze task was applied to analyze the working and cued reference memory in such offspring (P45). The real-time polymerase chain reaction results showed that prenatal morphine exposure caused significant decreases in mRNA levels of the PSD-95 and three NMDAR subunits (NR1, NR2A, and NR2B) in offspring (P14 and P45). Similarly, at the protein level, immunoblotting showed that decreased whole levels of PSD-95 and NMDAR subunits were seen in offspring subjected with prenatal morphine. Furthermore, the protein interaction of the synaptic complex between the PSD-95 and NMDAR subunit, as indicated by coimmunoprecipitation, was less in prenatal morphine samples than in vehicle controls (P14 and P45). The prenatal morphine group also showed poorer performance for an eight-arm radial maze task than the vehicle-control group. These results are particularly important for a better understanding of certain opioid-mediated neurobehavioral cognitive changes in offspring associated with altered protein interaction between PSD-95 and NMDAR subunits within the developing brain.

Ultrasound-guided radiofrequency neurotomy in cervical spine: sonoanatomic study of a new technique in cadavers.

AIM: To develop an ultrasound-guided technique for radiofrequency (RF) cervical medial branch neurotomy and to validate the accuracy of this new method. MATERIALS AND METHODS: Five non-embalmed, fresh cadavers were used; three male and two female cadavers with a median age at death of 67.2 years (range 50-84 years). This study was conducted in two parts. First, two of the cadavers were used to define the sonographic target point for RF cervical medial branch neurotomy using high-resolution ultrasound (12 to 5 MHz). The needles were guided to five consecutive cervical medial branches in the cadavers under ultrasound guidance. Subsequently, the position of the ultrasound-guided needle was verified using C-arm fluoroscopy. Ultrasound-guided RF neurotomy was performed to the C5 medial branches in all five cadavers. In the three cadavers not used in the first part of the study, ultrasound-guided RF neurotomy without C-arm fluoroscopic confirmation was performed to the C3-C7 medial branches. The accuracy of neurotomy was assessed by pathological examination of the cervical medial branches obtained through cadaver dissection. RESULTS: In all five cadavers, the sonographic target point was identified in all C3-C7 segments with the 12 to 5 MHz linear transducer. In all 20 needle placements for the first and second cadavers, C-arm fluoroscopy validated proper needle tip positions. In all five cadavers, successful neurotomy was pathologically confirmed in 30 of 34 cervical medial branches. CONCLUSIONS: Ultrasound-guided cervical medial branch neurotomy was successfully performed in 30 of 34 cervical medial branches in five cadavers. However, before eliminating fluoroscopic validation of final needle tip positioning, the technique should be validated in symptomatic patients.

Hypopharyngeal cancer treatment based on definitive radiotherapy: who is suitable for laryngeal preservation?

AIMS: To investigate prognostic factors for survival and locoregional control in patients with stage I-IVA hypopharyngeal cancer treated with laryngeal preservation radiotherapy. METHODS: This study was a retrospective analysis of 108 patients with stage I-IVA squamous cell carcinoma of the hypopharynx, treated with laryngeal preservation radiotherapy. Actuarial survival, disease-specific survival and local relapse-free survival were calculated, and multivariate analyses were performed using Cox's proportional hazards model. RESULTS: After a median follow-up duration of 39 months, the five-year local relapse-free survival rate was 35 per cent for all patients, 66 per cent for those with stage I-II disease, 46 per cent for those with stage III disease and 20 per cent for those with stage IVA disease (p = 0.004). Multivariate analyses showed that tumour and node stages were independent prognostic factors. CONCLUSIONS: Patients with stage I-II disease were suitable for laryngeal preservation radiotherapy. For most patients with stage III-IVA disease, other than those who were T1 N1 or T2 N1, the treatment results were poor.

Early stage cervical cancer with negative pelvic lymph nodes: pattern of failure and complication following radical hysterectomy and adjuvant radiotherapy.

PURPOSE OF INVESTIGATION: The objective was to optimize the adjuvant treatment for patients with lymph node negative cervical cancer by analyzing patterns of failure and complications following radical hysterectomy and adjuvant radiotherapy. METHODS: From September 1992 to December 1998, 67 patients with lymph node negative uterine cervical cancer (FIGO stage distribution: 50 Ib. 17 IIa), who had undergone radical hysterectomy and postoperative adjuvant radiotherapy with a minimum of three years of follow-up were evaluated. All patients received 50-58 Gy of external radiation to the lower pelvis followed by two sessions of intravaginal brachytherapy with a prescribed dose of 7.5 Gy to the vaginal mucosa. For 21 patients with lymphovascular invasion, the initial irradiation field included the whole pelvis for 44 Gy. The data were analyzed for actuarial survival (AS), pelvic relapse-free survival (PRFS), distant metastasis-free survival (DMFS), and treatment-related complications. Multivariate analysis was performed to assess the prognostic factors. RESULTS: The respective five-year AS, PRFS, and DMFS for the 67 patients were 79%, 93% and 87%. Multivariate analysis identified two prognostic factors for AS: bulky tumor vs non-bulky tumor (p = 0.003), positive resection margin (p = 0.03). The independent prognostic factors for DMFS was bulky tumor (p = 0.003), while lymphatic permeation showed marginal impact to DMFS (p = 0.08). The incidence of RTOG grade 1-4 rectal and non-rectal gastrointestinal complication rates were 20.9% and 19.4%, respectively. The independent prognostic factor for gastrointestinal complication was age over 60 years (p = 0.047, relative risk 4.1, 95% CI 1.2 approximately 11.7). The incidence of non-rectal gastrointestinal injury for the patients receiving whole pelvic radiation and lower pelvic radiation was 28.5% and 15.2%, respectively (p = 0.25). CONCLUSION: For patients with lymph node negative cervical cancer following radical hysterectomy, adjuvant lower pelvic radiation appears to be effective for pelvic control. It is also imperative to intensify the strategies of adjuvant therapy for some subgroups of patients.

Comparing whole body (18)F-2-deoxyglucose positron emission tomography and technetium-99m methylene diphosphonate bone scan to detect bone metastases in patients with breast cancer.

PURPOSE: At present, bone metastases are usually assessed using conventional technetium-99m methylene diphosphonate whole-body bone scan, which has a high sensitivity but a poor specificity. However, positron emission tomography with (18)F-2-deoxyglucose (FDG-PET) can offer superior spatial resolution and improved specificity. We attempted to evaluate the usefulness of FDG-PET for detecting bone metastases in breast cancer and to compare FDG-PET results with bone scan findings. PATIENTS: The study group comprised 48 patients with biopsy-proven breast cancer and suspected of having bone metastases who underwent bone scan and FDG-PET to detect the bone metastases. The final diagnosis of bone metastases was established by operative, histopathological findings or during a clinical follow-up longer than 1 year by additional radiographs or following FDG-PET/bone scan findings showing progressive widespread bone lesions. RESULTS: A total of 127 bone lesions including 105 metastatic and 22 benign bone lesions found by either FDG-PET or bone scan were evaluated. Using FDG-PET, 100 metastatic and 20 benign bone lesions were accurately diagnosed, and using bone scan 98 metastatic and 2 benign bone lesions were accurately diagnosed. The diagnostic sensitivity and accuracy of FDG-PET were 95.2% and 94.5%, and of bone scan were 93.3% and 78.7%, respectively. CONCLUSIONS: Our findings suggest that FDG-PET shows a similar sensitivity and a better accuracy than bone scan for detecting bone metastases in patients with breast cancer.