Randomized phase II trial of gemcitabine-cisplatin with or without trastuzumab in HER2-positive non-small-cell lung cancer.

BACKGROUND: Trastuzumab provides significant clinical benefits in HER2-positive metastatic breast cancer patients when administered in combination with chemotherapy. Chemotherapy has also been shown to be beneficial in some patients with advanced non-small-cell lung cancer (NSCLC). The present randomized phase II trial examined the effect of adding trastuzumab to a standard chemotherapeutic combination (gemcitabine-cisplatin) in patients with HER2-positive NSCLC. PATIENTS AND METHODS: Patients with untreated stage IIIB/IV HER2-positive NSCLC received up to six 21-day cycles of gemcitabine 1250 mg/m(2) (days 1 and 8) and cisplatin 75 mg/m(2) (day 1). Patients in the trastuzumab arm received trastuzumab 4 mg/kg intravenously (i.v.) followed by 2 mg/kg/week i.v. until progression. RESULTS: Of 619 patients screened, 103 were eligible. Fifty-one patients were treated with trastuzumab plus gemcitabine-cisplatin and 50 with gemcitabine-cisplatin alone. Efficacy was similar in the trastuzumab and control arms: response rate 36% versus 41%; median time to progression 6.3 versus 7.2 months; and median progression-free survival (PFS) 6.1 versus 7 months. Response rate (83%) and median PFS (8.5 months) appeared relatively good in the six trastuzumab-treated patients with HER2 3+ or fluorescence in situ hybridization (FISH)-positive NSCLC. Addition of trastuzumab to gemcitabine-cisplatin was well tolerated, side-effects were as expected, and trastuzumab did not exacerbate the known toxicity of gemcitabine and cisplatin. Symptomatic cardiotoxicity was observed in one trastuzumab-treated patient. Serum trastuzumab concentrations in the presence of gemcitabine-cisplatin were comparable to those of trastuzumab alone. CONCLUSIONS: Trastuzumab plus gemcitabine-cisplatin is well tolerated. Clinical benefit was not observed. Although HER2 3+/FISH-positive patients may benefit from trastuzumab, the subgroup is too small to provide definitive information. No significant effect of gemcitabine-cisplatin on trastuzumab pharmacokinetics was observed.     

Feminized Behavior and Brain Gene Expression in a Novel Mouse Model of Klinefelter Syndrome

Klinefelter Syndrome (KS) is the most common sex chromosome aneuploidy in men and is characterized by the presence of an additional X chromosome (XXY). In some Klinefelter males, certain traits may be feminized or shifted from the male-typical pattern towards a more female-typical one. Among them might be partner choice, one of the most sexually dimorphic traits in the animal kingdom. We investigated the extent of feminization in XXY male mice (XXYM) in partner preference and gene expression in the bed nucleus of the stria terminalis/preoptic area and the striatum in mice from the Sex Chromosome Trisomy model. We tested for partner preference using a three-chambered apparatus in which the test mouse was free to choose between stimulus animals of either sex. We found that partner preference in XXYM was feminized. These differences were likely due to interactions of the additional X chromosome with the Y. We also discovered genes that differed in expression in XXYM versus XYM. Some of these genes are feminized in their expression pattern. Lastly, we also identified genes that differed only between XXYM versus XYM and not XXM versus XYM. Genes that are both feminized and unique to XXYM versus XYM represent strong candidates for dissecting the molecular pathways responsible for phenotypes present in KS/XXYM but not XXM. In sum, our results demonstrated that investigating behavioral and molecular feminization in XXY males can provide crucial information about the pathophysiology of KS and may aid our understanding of sex differences in brain and behavior.     

Homologous Recombination Deficiency: Concepts,Definitions, and Assays

BackgroundHomologous recombination deficiency (HRD) is a phenotype that is characterized by the inability of a cell to effectively repair DNA double-strand breaks using the homologous recombination repair (HRR) pathway. Loss-of-function genes involved in this pathway can sensitize tumors to poly(adenosine diphosphate [ADP]-ribose) polymerase (PARP) inhibitors and platinum-based chemotherapy, which target the destruction of cancer cells by working in concert with HRD through synthetic lethality. However, to identify patients with these tumors, it is vital to understand how to best measure homologous repair (HR) status and to characterize the level of alignment in these measurements across different diagnostic platforms. A key current challenge is that there is no standardized method to define, measure, and report HR status using diagnostics in the clinical setting.MethodsFriends of Cancer Research convened a consortium of project partners from key healthcare sectors to address concerns about the lack of consistency in the way HRD is defined and methods for measuring HR status.ResultsThis publication provides findings from the group’s discussions that identified opportunities to align the definition of HRD and the parameters that contribute to the determination of HR status. The consortium proposed recommendations and best practices to benefit the broader cancer community.ConclusionOverall, this publication provides additional perspectives for scientist, physician, laboratory, and patient communities to contextualize the definition of HRD and various platforms that are used to measure HRD in tumors.     

Should we change our approach to resuscitating victims of femoral fracture?A clinical experience in a busy trauma hospital in Shiraz,Iran

Purpose Traumatic hemorrhagic shock is a life-threatening event worldwide.Severe brain trauma accompanying femoral fractures can trigger inflammatory responses in the body and increase pre-inflammatory cytokines such as TNF-α,IL-1.The primary treatment in these cases is hydration with crystalloids,which has both benefits and complications.The purpose of this study was to investigate the effects of fluid therapy on the hemodynamics,coagulation profiles,and blood gases in such patients.Methods In this cross-sectional study,patients were divided into two groups:femoral fracture group and non-femoral group.The hemodynamic status,coagulation profile,and blood gases of patients in both groups were evaluated upon arrival at the hospital and again 2 h later.Data were analyzed by t-test and ANOVA with repeated data and paired samples t-test.Results A total of 681 trauma patients(605 men and 76 women)participated in this study,including 69(86.3%)men and 11(13.8%)women in femoral fracture group and 536 men(89.2%)and 65 women(10.8%)in non-femoral group.The laboratory parameters were evaluated in response to the equal amount of crystalloid fluid given upon arrival and 2 h later.Blood gases decreased in the fracture group despite fluid therapy(p<0.003),and the coagulation profile worsened although the change was not statistically significant.Conclusion The treatment of multiple-trauma patients with femoral bone fractures should be more concerned with the need for the infusion of vasopressors such as norepinephrine.If there is evidence of clinical shock,excessive crystalloid infusion(limited to 1 L)should be avoided,and blood and blood products should be started as soon as possible.     

The effect of intraoperative retinal manipulation on the underlying retinal pigment epithelium: an experimental study

PURPOSE: Retinal pigment epithelial changes described after vitreoretinal surgery may result from localized compression injury caused by intentional or inadvertent contact with vitreoretinal instruments. The authors evaluated these changes resulting from manipulation of the retina without frank retinal injury. METHODS: One eye each of six pigmented rabbits underwent surgery during which the inner retinal surface was touched at several points with a 20-gauge silicone-tipped subretinal fluid cannula without causing a retinal break or subretinal hemorrhage. The rabbits were followed-up with indirect ophthalmoscopy, fundus photography, and fluorescein angiography, and were killed at 1 hour, 1 week, or 2 weeks. Light microscopy was used for histopathologic evaluation. RESULTS: On fluorescein angiography, diffuse leakage noted at the injury sites significantly decreased by the fourth day and almost completely disappeared by the second week. Disruption of photoreceptor outer segments and retinal pigment epithelium in the early specimens, and irregular pigmentation, proliferation, and migration of the retinal pigment epithelium at 1 and 2 weeks were the prominent features on histopathologic examination. CONCLUSIONS: Intraoperative manipulation of the attached retina may cause significant pigment epithelium displacement and proliferation and varying degrees of disorganization of normal retinal architecture in the absence of clinically evident retinal breaks and subretinal hemorrhages.     

User Satisfaction with Computerized Order Entry System and Its Effect on Workplace Level of Stress

To evaluate the impact of Computerized Provider Order Entry (CPOE) on workplace stress and overall job performance, as perceived by medical students, housestaff, attending physicians and nurses, after CPOE implementation at Penn State—Milton S. Hershey Medical Center, an academic tertiary care facility, in 2005. Using an online survey, the authors studied attitudes towards CPOE among 862 health care professionals. The main outcome measures were job performance and perceived stress levels. Statistical analyses were conducted using the Statistical Analytical Software (SAS Inc, Carey, NC). A total of 413 respondents completed the entire survey (47.9 % response rate). Respondents in the younger age group were more familiar with the system, used it more frequently, and were more satisfied with it. Interns and residents were the most satisfied groups with the system, while attending physicians expressed the least satisfaction. Attending physicians and fellows found the system least user friendly compared with other groups, and also tended to express more stress and frustration with the system. Participants with previous CPOE experience were more familiar with the system, would use the system more frequently and were more likely to perceive the system as user friendly. User satisfaction with CPOE increases by familiarity and frequent use of the system. Improvement in system characteristics and avoidance of confusing terminology and inconsistent display of data is expected to enhance user satisfaction. Training in the use of CPOE should start early, ideally integrated into medical and nursing school curricula and form a continuous, long-term and user-specific process. This is expected to increase familiarity with the system, reducing stress and leading to improved user satisfaction and to subsequent enhanced safety and efficiency.     

Bayesian model search for mixture models based on optimizing variational bounds

When learning a mixture model, we suffer from the local optima and model structure determination problems. In this paper, we present a method for simultaneously solving these problems based on the variational Bayesian (VB) framework. First, in the VB framework, we derive an objective function that can simultaneously optimize both model parameter distributions and model structure. Next, focusing on mixture models, we present a deterministic algorithm to approximately optimize the objective function by using the idea of the split and merge operations which we previously proposed within the maximum likelihood framework. Then, we apply the method to mixture of expers (MoE) models to experimentally show that the proposed method can find the optimal number of experts of a MoE while avoiding local maxima.