Valor predictivo de los índices 18F-FDG PET/TC sobre la carga tumoral residual en pacientes con cáncer de mama extenso tratadas con quimioterapia neoadyuvante / Predictive value of 18F-FDG PET/CT indices on extensive residual cancer burden in breast cancer patients treated with neoadjuvant chemotherapy

Objetivo: Investigamos la correlación entre los índices de PET/TC con 18F-FDG y la respuesta patológica en el cáncer de mama tratado con quimioterapia neoadyuvante (QNA), que se puntuó con el sistema de carga de cáncer residual (RCB) después de la cirugía. Nuestro objetivo es detectar antes una carga extensa de cáncer residual mediante el uso de los índices de PET/TC. Métodos: Se recuperaron las características de las pacientes de forma retrospectiva. Se calculó el valor máximo de captación estándar (SUVmáx), el volumen metabólico del tumor (MTV) y los índices de glucólisis total de la lesión (TLG), así como la tasa de reducción (RR) entre la línea de base y la evaluación intermedia, con la exploración FDG PET/TC. Todos los pacientes fueron evaluados según las puntuaciones RCB después de la cirugía. Las respuestas patológicas y los resultados de las mediciones de PET/TC se analizaron con parámetros demográficos y clínicos. Resultados: Un total de 95 pacientes fueron incluidos en el estudio. Según las respuestas patológicas, la distribución de RCB-0, -1, -2, -3 fue de 13 (13,7%), 11 (11,6%), 30 (31,6%) y 41 (43,2%), respectivamente. La supervivencia libre de enfermedad fue significativamente menor en el grupo RCB-3 en comparación con el grupo de respuesta patológica (p=0,01). Según el análisis multivariante, se determinó que el RR del SUVmáx era una variable independiente que predecía la RCB extensa con un valor de corte óptimo del 86% (p<0,05). Conclusiones: Determinamos el RR de SUVmáx como un factor independiente para predecir la carga tumoral residual extensa. Creemos que el RR de SUVmáx es suficiente para predecir la respuesta patológica en la práctica diaria. Además, las mediciones de MTV y TLG no contribuyen adicionalmente al SUVmáx por sí solas y pueden causar una pérdida de trabajo innecesaria (AU)

Aim: We investigated the correlation between 18F-FDG PET/CT indices and pathological response in breast cancer treated with neoadjuvant chemotherapy (NACT) which was scored with Residual Cancer Burden (RCB) system after surgery. Our aim is to detect extensive residual cancer burden earlier by using PET/CT indices. Methods: Characteristics of patients were retrieved retrospectively. Baseline maximum Standart Uptake Value (SUVmax), Metabolic Tumor Volume (MTV) and Total Lesion Glycolysis (TLG) indices and reduction rate (RR) between baseline and interim evaluation were calculated with FDG PET/CT scan. All patients were evaluated according to RCB scores after surgery. Pathological responses and PET/CT measurement results were analyzed with demographic and clinical parameters. Results: A total of 95 patients were included in the study. According to pathological responses, the distribution of RCB-0, -1, -2, -3 were 13 (13.7%), 11 (11.6%), 30 (31.6%), 41 (43.2%), respectively. Disease-free survival was significantly lower in the RCB-3 group compared to the pathological responder group (P=.01). According to multivariate analysis, RR of SUVmax was determined as an independent variable predicting extensive residual cancer burden with an optimal cut-off value of 86% (P<.05). Conclusions: We determined RR of SUVmax as an independent factor for predicting extensive residual tumor burden. We believe that RR of SUVmax is sufficient to predict pathological response in daily practice. In addition, MTV and TLG measurements do not contribute additionally to SUVmax alone and can cause unnecessary labor loss (AU)

Magnesium sulfate micro air pump suction for bronchiolitis treatment in infants under two years old.

OBJECTIVE: To investigate the efficiency, clinical effects and nursing methods related to the use of magnesium sulfate micro air pump suction for treating infants under two years old suffering from bronchiolitis. PATIENTS AND METHODS: From January 2014 to September 2014, ninety-six infants with capillary bronchitis were enrolled. Patients were randomly divided into two groups: experimental group (n=49) and control group (n=47). All patients went through conventional anti-inflammatory therapy. Based on this, infants in the control group were additionally treated with intravenous drip of magnesium sulfate while patients in the experimental group were treated with magnesium sulfate micro air pump suction. We recorded all changes in blood gas and clinical scores, the residence time of symptoms and signs of bronchiolitis, and hospitalization time. Results obtained on clinical effects and adverse reactions were compared and analyzed. RESULTS: The Variations of PaO2, PaCO2, SaO2 before treatment in both groups did not show any statistically significant differences (p>0.05); while after treatment analyses demonstrated that in both groups we had an increase in PaO2 and SaO2 and a decrease in PaCO2. The increase in PaO2 and SaO2 values were more pronounced while the decrease observed in PaCO2 was more significant in our experimental group. The total effective rate was significantly higher while the total adverse reaction rate, the resolution time of clinical symptoms and hospitalization time were significantly lower in our experimental group. CONCLUSIONS: Magnesium sulfate micro air pump suction was safe and effective in treating with bronchiolitis of infants below 2 years old, and its adverse reaction rate was low, nursing procedure was simple, and nursing difficulty level was low.

Can postmortem MRI be used to assess trajectories in gunshot victims?

PURPOSE: Multi-detector computed tomography (MDCT) has proven to be of value for the reconstruction of trajectories of projectiles and the assessment of the injuries in deceased gunshot victim. For the depiction of soft tissue injury, MRI is superior to MDCT and MRI may be of value to assess trajectories. In a clinical setting, there are guidelines for the application of MRI in patients with projectiles or projectile fragments and with precautions MRI is safe for these patients. However, this has not been studied for the postmortem application of MRI from a forensic point of view. SUBJECTS AND METHOD: To assess the behaviour of projectiles, two ferromagnetic and one non-ferromagnetic projectile were exposed to the magnetic field of a 1.5- and 3-T MRI. Projectiles were placed in six phantoms with the characteristics of human muscle tissue, with and without a simulated trajectory in the gel. Before and after exposure to the magnetic field, the gelatine phantoms were imaged with MDCT to assess the position of the projectiles. RESULTS: The ferromagnetic projectiles rotate to a position where their long axis is parallel to the z-axis of the magnetic field and five out of the six projectiles moved through, either through the simulated trajectory or through a new trajectory. This was observed in both the 1.5- and 3-T systems. CONCLUSION: Ferromagnetic projectiles can rotate and migrate in a gelatine phantom. It is very likely that these projectiles will also migrate in a human body in a MRI system. Therefore, from a forensic point of view, postmortem MR will make a reconstruction of the trajectories in the body and of the reconstruction of the incident as a whole less reliable.

Novel lentiviral-inducible transgene expression systems and versatile single-plasmid reporters for in vitro and in vivo cancer biology studies.

Many of the cancer cell lines derived from solid tumors are difficult to transfect using commonly established transfection approaches. This hurdle for some DNA transfection systems has hindered cancer biology studies. Moreover, there are limited tools for studying pathway activities. Therefore, highly efficient improved gene transfer and versatile genetic tools are required. In this study, we established and developed a comprehensive set of new lentiviral tools to study gene functions and pathway activities. Using the optimized conditions, cancer cell lines achieved >90% transduction efficiency. Novel lentiviral doxycycline-regulated pTet-IRES-EGFP (pTIE) systems for transgene expression and TRE reporters used for pathway activity determination were developed and tested. The pTIE Tet-Off system showed in vitro doxycycline-sensitive responses with low or undetectable leakage of protein expression and in vivo tumor suppression as illustrated using candidate tumor suppressors, Fibulin-2 and THY1. In contrast, the Tet-On system showed dose-dependent responses. The pTRE-EGFP (pTE) and pTRE-FLuc-EF1α-RLuc (pT-FER) reporters with the NFκB p65 subunit consensus sequence showed GFP and firefly luciferase responses, which were directly correlated with TNFα stimulation, respectively. Taken together, these newly developed lentiviral systems provide versatile in vitro and in vivo platforms to strengthen our capabilities for cancer biology studies.

Anti-angiogenic pathway associations of the 3p21.3 mapped BLU gene in nasopharyngeal carcinoma.

Zinc-finger, MYND-type containing 10 (ZMYND10), or more commonly called BLU, expression is frequently downregulated in nasopharyngeal carcinoma (NPC) and many other tumors due to promoter hypermethylation. Functional evidence shows that the BLU gene inhibits tumor growth in animal assays, but the detailed molecular mechanism responsible for this is still not well understood. In current studies, we find that 93.5% of early-stage primary NPC tumors show downregulated BLU expression. Using a PCR array, overexpression of the BLU gene was correlated to the angiogenesis network in NPC cells. Moreover, expression changes of the MMP family, VEGF and TSP1, were often detected in different stages of NPC, suggesting the possibility that BLU may be directly involved in the microenvironment and anti-angiogenic activity in NPC development. Compared with vector-alone control cells, BLU stable transfectants, derived from poorly-differentiated NPC HONE1 cells, suppress VEGF165, VEGF189 and TSP1 expression at both the RNA and protein levels, and significantly reduce the secreted VEGF protein in these cells, reflecting an unknown regulatory mechanism mediated by the BLU gene in NPC. Cells expressing BLU inhibited cellular invasion, migration and tube formation. These in vitro results were further confirmed by in vivo tumor suppression and a matrigel plug angiogenesis assay in nude mice. Tube-forming ability was clearly inhibited, when the BLU gene is expressed in these cells. Up to 70-90% of injected tumor cells expressing increased exogenous BLU underwent cell death in animal assays. Overexpressed BLU only inhibited VEGF165 expression in differentiated squamous NPC HK1 cells, but also showed an anti-angiogenic effect in the animal assay, revealing a complicated mechanism regulating angiogenesis and the microenvironment in different NPC cell lines. Results of these studies indicate that alteration of BLU gene expression influences anti-angiogenesis pathways and is important for the development of NPC.

SAA1 polymorphisms are associated with variation in antiangiogenic and tumor-suppressive activities in nasopharyngeal carcinoma.

Nasopharyngeal carcinoma (NPC) is a cancer that occurs in high frequency in Southern China. A previous functional complementation approach and the subsequent cDNA microarray analysis have identified that serum amyloid A1 (SAA1) is an NPC candidate tumor suppressor gene. SAA1 belongs to a family of acute-phase proteins that are encoded by five polymorphic coding alleles. The SAA1 genotyping results showed that only three SAA1 isoforms (SAA1.1, 1.3 and 1.5) were observed in both Hong Kong NPC patients and healthy individuals. This study aims to determine the functional role of SAA1 polymorphisms in tumor progression and to investigate the relationship between SAA1 polymorphisms and NPC risk. Indeed, we have shown that restoration of SAA1.1 and 1.3 in the SAA1-deficient NPC cell lines could suppress tumor formation and angiogenesis in vitro and in vivo. The secreted SAA1.1 and SAA1.3 proteins can block cell adhesion and induce apoptosis in the vascular endothelial cells. In contrast, the SAA1.5 cannot induce apoptosis or inhibit angiogenesis because of its weaker binding affinity to αVß3 integrin. This can explain why SAA1.5 has no tumor-suppressive effects. Furthermore, the NPC tumors with this particular SAA1.5/1.5 genotype showed higher levels of SAA1 gene expression, and SAA1.1 and 1.3 alleles were preferentially inactivated in tumor tissues that were examined. These findings further strengthen the conclusion for the defective function of SAA1.5 in suppression of tumor formation and angiogenesis. Interestingly, the frequency of the SAA1.5/1.5 genotype in NPC patients was ~2-fold higher than in the healthy individuals (P=0.00128, odds ratio=2.28), which indicates that this SAA1 genotype is significantly associated with a higher NPC risk. Collectively, this homozygous SAA1.5/1.5 genotype appears to be a recessive susceptibility gene, which has lost the antiangiogenic function, whereas SAA1.1 and SAA1.3 are the dominant alleles of the tumor suppressor phenotype.

General anesthesia for cesarean section in a Singapore maternity hospital: a retrospective survey.

We conducted a retrospective study of all cases of cesarean section at the KK Women's and Children's Hospital over a one-year period from September 1, 2002 to August 31, 2003, with the aim of evaluating current anesthetic practice. These cases were identified using hospital databases and relevant data was extracted from clinical notes. There were 14244 deliveries during the study period with a cesarean section rate of 25.2% (3583 cases). Of these, 20.4% (732 cases) were performed under general anesthesia. Maternal request was the chief reason for general anesthesia, especially among elective cases. Regional block failure accounted for 16% of the general anesthesia cases performed or 4.0% of the total regional techniques attempted. Regional block failure rate was highest for emergency cases in which an indwelling labor epidural catheter was used to provide surgical anesthesia via a bolus top-up. General anesthesia still has a definite place for cesarean delivery despite the predominant use of regional techniques in our institution.

Free-floating cryostat sections for immunoelectron microscopy: Bridging the gap from light to electron microscopy.

Frozen skin sections are routinely used for light microscopic immunohistochemical study of the skin basement membrane zone for two reasons: some skin basement membrane zone proteins are labile to routine chemical fixation, and skin is not amenable to vibratome sectioning. However, inherent limitations of conventional frozen sections, including compromised morphology and a requirement for glass slide-mounting, usually limit immunohistochemical study to the light microscopy level. In the present study, we introduce use of unfixed, free-floating cryostat sections for characterization of immunolocalizations of selected skin basement membrane proteins at both the light and electron microscopy level. The new procedure employs free-floating cryostat sections that can be processed as routine tissue specimens and can be subjected to a variety of special staining procedures including immunohistochemistry. Especially useful is the ease of progressive processing of the same tissue specimen from light microscopy to electron microscopy. In this regard, the method renders itself useful when results of immunolabeling experiments need to be elucidated quickly at histological and ultrastructural levels as required for diagnostic and accelerated investigative strategies.

Intrauterine growth in the offspring of epileptic women: a prospective multicenter study.

The aim of the present study was to evaluate the risk of intrauterine growth delay in the offspring of epileptic mothers and to quantify the risks of intrauterine exposure to antiepileptic drugs (AEDs). Data concerning 870 newborns, prospectively collected in Canada, Japan and Italy, using the same study design, were pooled and analyzed. The overall proportion of newborns whose body weight (7.8%) or head circumference (11.1%) at birth were below the 10th percentile was not increased. However, logistic regression analysis showed that the risk of small head circumference was significantly higher in Italian than in Japanese (RR 4.2; 95% CI: 2.2-8.0) or Canadian children (RR 2.6; 95% CI: 1.1-6.5), and in children exposed to polytherapy (RR 2.7; 95% CI: 1.2-6.3), phenobarbital (PB) (RR 3.6; 95% CI: 1.4-9.4) and primidone (PRM) (RR 4.5; 95% CI: 1.5-13.8). Country was also the only factor affecting low body weight, with Italian children having a higher risk than Japanese (RR 5.2; 95% CI: 2.6-10.4) or Canadian (RR 8.8; 95% CI: 2.0-38.1) children. Due to the small categories, the influence of AED doses and plasma concentrations was studied for each individual AED, without adjustment for the other potential confounding factors. A clear dose-dependent effect was found for PB and PRM in terms of both small head circumference and low body weight, and a concentration-dependent effect for PB in terms of small head circumferences. The size of the difference between the Italian and the other two populations, which is only partially explained by differences in therapeutic regimens, suggests that genetic, environmental and ethnic factors also need to be taken into account when considering possible explanations.

Congenital malformations due to antiepileptic drugs.

To identify the major risk factors for the increased incidence of congenital malformations in offspring of mothers being treated for epilepsy with antiepileptic drugs (AEDs) during pregnancy and, to determine the relative teratogenic risk of AEDs, we prospectively analyzed 983 offspring born in Japan, Italy, and Canada. The incidence of congenital malformations in offspring without drug exposure was 3.1%, versus an incidence with drug exposure of 9.0%. The highest incidence in offspring exposed to a single AED occurred with primidone (PRM; 14.3%), which was followed by valproate (VPA; 11.1%), phenytoin (PHT; 9.1%), carbamazepine (CBZ; 5.7%), and phenobarbital (PB; 5.1%). The VPA dose and level positively correlated with the incidence of malformations. This study first determined a cut-off value of VPA dose and level at 1000 mg/day and 70 microg/ml, respectively, to avoid the occurrence of malformations. The incidence of malformations increases as the number of drugs increases, and as the total daily dose increases. Specific combinations of AEDs such as VPA + CBZ and PHT + PRM + PB produced a higher incidence of congenital malformations. The incidence of malformations was not associated with any background factors studied except for the presence of malformations in siblings. These results indicate that the increased incidence of congenital malformations was caused primarily by AEDs, suggesting that malformations can be prevented by improvements in drug regimen, and by avoiding polypharmacy and high levels of VPA (more than 70 microg/ml) in the treatment of epileptic women of childbearimg age.

Intravenous remifentanil: placental transfer, maternal and neonatal effects.

BACKGROUND: Remifentanil has not been studied in obstetric patients. This study evaluates the placental transfer of remifentanil and the neonatal effects when administered as an intravenous infusion. METHODS: Nineteen parturients underwent nonemergent cesarean section with epidural anesthesia and received 0.1 microg kg(-1) x min(-1) remifentanil intravenously, which was continued until skin closure. Maternal arterial (MA), umbilical arterial (UA), and umbilical venous (UV) blood samples were obtained at delivery for analysis of drug concentrations of remifentanil, its metabolite, and blood gases. Maternal vital signs were monitored continuously, and pain and sedation levels were assessed intermittently. Apgar scores were obtained at 1, 5, 10, and 20 min, and Neonatal and Adaptive Capacity Scores were noted 30 and 60 min after delivery. Parturients and newborns were observed for at least 24 h after surgery for side effects. RESULTS: The means and SDs of UV:MA and UA:UV ratios for remifentanil were 0.88+/-0.78 and 0.29+/-0.07, respectively. Mean clearance was 93 ml x min(-1) kg(-1). The mean UV:MA and UA:MV ratios for remifentanil acid were 0.56+/-0.29 and 1.23+/-0.89, respectively. The mean MA (remifentanil acid):MA (remifentanil) ratio was 2.92+/-3.65. There were no adverse effects on the neonates, but there was a sedative effect and respiratory depressant effect on the mothers. CONCLUSIONS: Remifentanil crosses the placenta but appears to be rapidly metabolized, redistributed, or both. Maternal sedation and respiratory changes occur, but without adverse neonatal or maternal effects.

Predictors of bone mineral loss in patients with ovarian cancer treated with anticancer agents.

OBJECTIVE: To identify factors predicting bone mineral loss during anticancer chemotherapy. METHODS: Fifteen women (mean age 38.2 +/- 7.8 years; range 30-46 years) with ovarian cancer who had been treated with cisplatin-adriamycin-cyclophosphamide for six cycles every 4 weeks following surgical cytoreductin were studied. Bone mineral density (BMD) of the lumbar spine (L2-L4) was measured by dual-energy x-ray absorptiometry before and after chemotherapy. Fifteen age-matched women whose ovaries had been removed surgically for other reasons. served as controls. None of the patients had received hormonal treatment. The two groups were compared for percentage change of BMD (BMD%) over the same period. In the chemotherapy group, total fat mass, body fat ratio, total lean mass, percent lean, and ration of trunk fat to leg fat were measured by dual-energy x-ray absorptiometry. Lean loss during chemotherapy was also calculated. These variables were compared before and at the end of chemotherapy. Possible correlations of baseline variables with BMD% were determined in univariate and stepwise regression analysis. RESULTS: Mean ( +/- standard deviation) BMD decreased to 87.4 +/- 2.1% after six cycles of chemotherapy and 97.6 +/- 0.4% after 6 months in controls, but the greatest decrease was observed in the chemotherapy group (P < .001). Although baseline lean mass, baseline BMD, body weight, and lean loss during chemotherapy were correlated with BMD% in univariate analysis, baseline lean mass was still significant in stepwise regression analysis. CONCLUSION: Baseline lean mass predicts bone mineral lose with anticancer chemotherapy.

Echographia as a symptom of interictal state in an epileptic patient: a case report.

Echographia is a phenomenon in which a patient continuously translates verbal stimuli into writing. We encountered a patient with epilepsy who developed visual echographia during interictal periods. In this case, echographia was observed during two different periods, namely the period of disturbed consciousness after the epileptic seizure and the period of clear consciousness after suppression of the seizures. Disinhibition due to disturbance of the consciousness is considered to have been the cause of echographia in the former period. In the latter period, it is considered that echographia was caused by the release of lower function from suppression of upper function by brain dysfunction, as the after effect of status epilepticus. As echographia can be observed in epileptic patients, attention and careful observation by epileptologists is needed.

Microwave superheating enhances immunocytochemistry in the freshly frozen rat brain.

The goal of this study was to evaluate the effects of microwave irradiation on immunocytochemical staining in freshly frozen rat brain tissue using an antibody previously shown to successfully stain only formalin-fixed materials. GFAP immunoreactivity was markedly increased in sections exposed to microwave heating when compared with control tissue. Uniform staining enhancement was mainly a result of increased numbers of immunoreactive soma and large astrocytic processes. The integrity of the tissue was not affected by this treatment. Other antibodies need to be tested with this method, but our results suggest that microwave irradiation is useful for rapid antigen retrieval in freshly frozen central nervous system tissue.

Microdensitometric measures of cytoplasmic RNA and total protein in pyramidal neurons of the insular cortex and midfrontal gyrus in patients with Alzheimer's disease.

Scanning and integrating microdensitometry of azure B- and Coomassie brilliant blue G-stained tissue sections was used to measure the levels of RNA and protein, respectively, in pyramidal neurons of the insular cortex (INS) and midfrontal gyrus (MFG) in patients with Alzheimer's disease (AD) and age-matched, nondemented control subjects. AD was associated with a decreased neuronal RNA (by 7.4 per cent) and protein (by 28.7 per cent) content in INS. Although the neuronal RNA content was maintained at the control amounts in MFG, the average protein level was lower (14.7 per cent) in AD patients. These results demonstrate a disease-related impairment in metabolic function in two brain regions connected via discrete corticocortical pathways. Such findings support the hypothesis that a primary site of pathology occurs in AD, and specific neural deficits occur secondarily in certain connected brain regions.