Citations

ABSTRACTIntroductionPneumothorax is a potentially serious complication of electromyography (EMG). Data on the frequency of pneumothorax after EMG are lacking. The purpose of this study was to determine the frequency, timing, and risk factors for iatrogenic pneumothorax after EMG. Methods: Cases of pneumothorax after EMG were reviewed for clinical, electrophysiological, and radiological data. Results: Of 64,490 EMG studies, 7 patients had an association between the EMG and pneumothorax. All patients were symptomatic and presented within 24 hours of EMG. Sampling of serratus anterior and diaphragm was causative in 1 patient each. In 5 patients, multiple high‐risk muscles were sampled. The highest frequency of pneumothorax was observed with examination of serratus anterior (0.445%) and diaphragm (0.149%). Conclusions: The frequency of symptomatic iatrogenic pneumothorax after EMG appears to be low, and examinations of serratus anterior and diaphragm carry the highest risk. Electromyographers should be aware of the risk of pneumothorax and should counsel patients accordingly. Muscle Nerve 53: 518–521, 2016

ObjectivesThe aim of the present study was to engage a national advocacy group and local stakeholders for guidance in developing a bipolar disorder biobank through a web‐based survey and a community advisory board.MethodsThe Depression and Bipolar Support Alliance and the Mayo Clinic Bipolar Biobank conducted a national web‐based survey inquiring about interest in participating in a biobank (i.e., giving DNA and clinical information). A community advisory board was convened to guide establishment of the biobank and identify key deliverables from the research project and for the community.ResultsAmong 385 survey respondents, funding source (87%), professional opinion (76%), mental health consumer opinion (79%), and return of research results (91%) were believed to be important for considering study participation. Significantly more patients were willing to participate in a biobank managed by a university or clinic (78.2%) than one managed by government (63.4%) or industry (58.2%; both p < 0.001). The nine‐member community advisory board expressed interest in research to help predict the likelihood of bipolar disorder developing in a child of an affected parent and which medications to avoid. The advisory board endorsed the use of a comprehension questionnaire to evaluate participants' understanding of the study (e.g., longevity of DNA specimens, right to remove samples, accessing medical records) as a means to strengthen the informed consent process.ConclusionsThese national survey and community advisory data support the merit of establishing a biobank to enable studies of disease risk, provided that health records and research results are adequately protected. The goals of earlier diagnosis and individualized treatment of bipolar disorder were endorsed.

Nanoparticles emerged as carriers of promising diagnostic and therapeutic molecules due to their unique size, injectability, and potential to sustainably release molecular cargos.

Use of the Molecular Adsorbent Recirculating System (MARS) as a liver support device continues to grow worldwide. Various components of the MARS circuit remove both protein‐bound and water‐soluble molecules. Little is known about the extent of the enhanced clearance mechanisms used in MARS therapy on drug elimination. Of particular interest to acute care practitioners is the impact of MARS on antibiotic clearance, as suboptimal concentrations of such drugs can negatively impact patient outcomes. The properties of piperacillin/tazobactam suggest that elimination may be enhanced in the setting of MARS therapy. We describe two cases in which this was studied. Piperacillin concentrations were determined at various points within the MARS circuit, and patient serum concentrations were reported throughout the dosing interval while receiving MARS therapy. Piperacillin concentrations in both cases were in excess of the desired goal minimum inhibitory concentrations for treatment of gram‐negative infections. Use of an extended‐infusion strategy of piperacillin/tazobactam 3.375 or 4.5 g given every 8 hours maintained desired serum levels throughout the dosing interval. To our knowledge, this is the second published report on the use of piperacillin/tazobactam during MARS therapy. These case reports reveal successful dosing strategies for patients requiring piperacillin/tazobactam while receiving MARS therapy, as well as quantify the influence of individual MARS elements on drug extraction.

AbstractObjectiveA common concern of utilizing prenatal advanced genetic testing is that a result of uncertain clinical significance will increase patient anxiety. However, prenatal ultrasound may also yield findings of uncertain significance, such as ‘soft markers’ for fetal aneuploidy, or findings with variable prognosis, such as mild ventriculomegaly. In this study we compared risk perception following uncertain test results from each modality.MethodsA single survey with repeated measures design was administered to 133 pregnant women. It included ‘intolerance of uncertainty’ questions, two hypothetical scenarios involving prenatal ultrasound or advanced genetic testing, and response questions. The primary outcome was risk perception score.ResultsRisk perception did not vary significantly between ultrasound and genetic scenarios (p = 0.17). The genetic scenario scored a higher accuracy (p = 0.04) but lower sense of empowerment (p = 0.01). Furthermore, patients were more likely to seek additional testing after an ultrasound than after genetic testing (p = 0.05). There were no differences in other secondary outcomes including perception of life‐altering consequences and hypothetical worry, anxiety, confusion, or medical care decisions.ConclusionsOur data suggest that uncertain findings on prenatal genetic testing do not elicit a higher perception of risk or anxiety when compared to ultrasound findings of comparable uncertainty. © 2015 John Wiley & Sons, Ltd.

Abstract Rationale Cognitive dysfunction has been demonstrated in chronic obstructive pulmonary disease (COPD), but studies are limited to cross-sectional analyses or incompletely characterized populations. Objectives We examined longitudinal changes in sensitive measures of executive function in a well-characterized population of patients with severe COPD. Methods This study was performed on patients enrolled in the National Emphysema Treatment Trial. To assess executive function, we analyzed trail making (TM) A and B times at enrollment in the trial (2,128 patients), and at 12 (731 patients) and 24 months (593 patients) after enrollment, adjusted for surgery, marriage status, age, education, income, depression, PaO2, PaCO2, and smoking. Associations with survival and hospitalizations were examined using Cox regression and linear regression models. Measurements and Main Results The average age of the patients was 66.4 years, and the average FEV1 was 23.9% predicted. At the time of enrolment, 38% had executive dysfunction. Compared with those who did not, these patients were older, less educated, had higher oxygen use, higher PaCO2, worse quality of life as measured by the St. George’s Respiratory Quotient, reduced well-being, and lower social function. There was no significant change over 2 years in TM A or B times after adjustment for covariables. Changes in TM B times were modestly associated with survival, but changes in TM B − A times were not. Changes in TM scores were not associated with frequency of hospitalization. Lung function, PaO2, smoking, survival, and hospitalizations were not significantly different in those with executive dysfunction. Conclusions In this large population of patients with severe emphysema and heavy cigarette smoking exposure, there was no significant decline over 2 years in cognitive executive function as measured by TM tests. There was no association between executive function impairment and frequency of hospitalization, and there was a possible modest association with survival. It is plausible that cerebrovascular comorbidities explain previously described cognitive pathology in COPD.

Abstract Purpose: Treatment of recurrent ovarian cancer is limited by low response rates to salvage chemotherapy. Novel small molecule inhibitors to Chk1 (checkpoint kinase 1) have been proposed to potentiate the cytotoxic effect of one such salvage treatment, gemcitabine, by interrupting the DNA damage repair pathway. Patient derived tumorgrafts were characterized by responsiveness to gemcitabine +/- MK8776 (Chk1 inhibitor). Response was correlated with markers of Chk1 activity. Methods: Patient-derived tumorgraft models were created from patients undergoing surgery for epithelial ovarian cancer. Gemcitabine response was characterized in five high-grade serous models (PH044, PH048, PH070, PH080, and PH110). Two models (PH048 and PH080) were treated with gemcitabine monotherapy (240 mg/kg qweek x 4 doses), MK8776 monotherapy (32 mg/kg qweek x 4 doses), and with combination therapy (Gemcitabine 190 mg/kg and MK8776 32 mg/kg qweek x 4 doses). Animals were monitored for cytotoxicity, and tumors were measured weekly with ultrasound. Response to gemcitabine and to combination therapy was correlated to immunohistochemistry of γH2AX and immunoblotting for p345-Chk1 and p296-Chk1. Results: Gemcitabine monotherapy did not affect tumor growth in two models (PH044 and PH048). Significant in vivo response to gemcitabine was seen in PH070 and PH080. Significant growth attenuation but not tumor regression was seen in PH110. MK8776 did not have any effect on tumor growth as monotherapy or in combination with gemcitabine in the gemcitabine resistant model, PH048. In contrast, in a gemcitabine sensitive model, PH080, MK8776 monotherapy significantly attenuated tumor growth, and there was a trend for MK8776 to potentiate the cytotoxic effects of gemcitabine in PH080 (p=0.16). Final tumor weights in the PH080 model after 4 doses of chemotherapy were 1.7 g (90%CI: 1.5-1.9g), 0.3g (90%CI: 0.18-0.35g), and 0.14g (90%CI: 0.08-.19g) in the control, gemcitabine alone, and gemcitabine with MK8776 groups respectively. Decrease in the tumor auto-phosphorylation of Chk1 at Serine-296 was observed in some, but not all models in response to MK8766 treatment. γH2AX increased in response to the addition of MK8776 to gemcitabine. Conclusions: Chk1 inhibition may enhance the activity of gemcitabine in some, but not all ovarian tumors. Further work is needed to find markers that will predict response to Chk1 inhibitors to help select patients for future clinical trials. While pChk1-S296 previously demonstrated potential utility as a biomarker of Chk1 inhibition, in vivo assessments of its differential expression may demonstrate the unreliability of this marker. This work supports the use of patient derived tumorgrafts in drug development for ovarian cancer. Citation Format: A Kumar, S Weroha, M Becker, X Hou, S Greiner, L Karnitz, P Haluska. Chk1 inhibitor (MK8776) enhances cytotoxicity of gemcitabine in select patient-derived ovarian tumorgraft models [abstract]. In: Proceedings of the 10th Biennial Ovarian Cancer Research Symposium; Sep 8-9, 2014; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(16 Suppl):Abstract nr POSTER-THER-1419.

Abstract Purpose: It is well known that the immune system impacts the clinical course of ovarian cancer suggesting that immune-based approaches may effective in treating the disease. This has led to several clinical trials of novel treatments such as antibody, vaccine, and adoptive T cell therapy. PD-1:PD-L1 axis is a major immune regulatory pathway that blunts immune effectors in the tumor microenvironment. It is well known that high surface expression of PD-1 on tumor infiltrating T cells is a sign of their exhaustion. However, the complete mechanism behind the PD-1 regulation of T cell exhaustion is yet to be explored. Recently we identified that PD-1 is also expressed on ovarian tumor-infiltrating myeloid dendritic cells (DCs) that exhibit an immunosuppressive phenotype. Our goal in this study was to understand the mechanism by which PD-1 mediates the paralysis of ovarian cancer infiltrating DCs. Experimental procedures: PD-1+ DCs obtained from ID8 mouse model of ovarian cancer were used in this study. Data from this preclinical model was confirmed by using myeloid DCs obtained from ovarian cancer patient’s samples. Using standard flow cytometry, immunoassays (ELISA, multiplexed cytokine assay), PCR array, western blot and confocal microscopy, PD-1 mediated paralysis of ovarian cancer DCs was determined. Results: Our data shows that blockade of surface PD-1 on ovarian cancer infiltrating DCs results in their activation by, enhancing their surface co-stimulatory molecules expression, increasing their motility, enhancing their antigen presentation capacity, and increasing their production of immunostimulatory cytokines. Also, our results suggest that PD-1 expressed on tumor DCs mediates the suppression of NFkB which occurs through SHP-2 and IKK dependent mechanisms. Conclusion: Our study reveals that blockade of PD-1 on ovarian cancer infiltrating DCs results in the reversal of their paralysis to such an extent that it overrides their B7-H1 mediated suppression of T cells and this occurs through the reversal of PD-1 mediated tonic suppression of NFkB. Citation Format: Lavakumar Karyampudi James Krempski, Purushottam Lamichhane, Kimberly R. Kalli, Marshall D. Behrens, Doris M. Vargas, Lynn C Hartmann, Karen E Hedin, Ellen L. Goode, Keith L. Knutson. PD-1 mediated paralysis of ovarian cancer infiltrating dendritic cells [abstract]. In: Proceedings of the 10th Biennial Ovarian Cancer Research Symposium; Sep 8-9, 2014; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(16 Suppl):Abstract nr POSTER-THER-1418.

Abstract FoxM1, a member of the Forkhead transfection factors, has been found to be overexpressed in many human cancers including ovarian cancer. Although FoxM1 is known to be downregulated by p53, the molecular mechanisms are not well characterized. In this study, we used the MDM2 inhibitor Nutlin-3 as a tool to modulate p53 expression and investigated the mechanism by which p53 regulates FoxM1 expression in ovarian cancer cells. We observed that Nutlin-3 upregulated p53 protein and downregulated FoxM1 mRNA and protein levels in ovarian cancer cell lines with wild type TP53, but not in cell lines with mutant TP53. This effect was at least partially blocked by cycloheximide or actinomycin D, indicating a transcription- and translation-dependent mechanism. Pulse-chase studies revealed that downregulation of FoxM1 by Nutlin-3 is due to enhanced FoxM1 mRNA decay. Knockdown of p53 using shRNAs abrogated the suppression of FoxM1 expression by Nutlin-3, indicating a p53-dependent mechanism. Furthermore, silencing of FoxM1 by shRNAs in ovarian cancer cells with or without wild-type TP53 led to a significant decrease in cell proliferation. The FoxM1 inhibitor, thiostrepton, induces cytotoxicity in ovarian cancer cell lines and enhances sensitivity to cisplatin in these cells. Thiostrepton downregulates FoxM1 expression in several ovarian cancer cell lines and enhances sensitivity to carboplatin in vivo. Finally, FoxM1 expression is elevated in nearly all (47/48) ovarian tumors. In summary, the present study provides novel evidence that p53 downregulates FoxM1 in ovarian cancer cells at least in part by destabilizing FoxM1 mRNA and that FoxM1 may be targeted for therapeutic benefits in ovarian cancer. Citation Format: Xuan Zhang, Lihua Cheng, Kay Minn, Magdalena Waggoner, Nikhil K. Parelkar, Iman Jokar, George A. Vielhauer, Rashna Madan, Andrew K. Godwin, Viji Shridhar,, Jeremy Chien. Targeting p53-FoxM1 axis in ovarian cancer [abstract]. In: Proceedings of the 10th Biennial Ovarian Cancer Research Symposium; Sep 8-9, 2014; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(16 Suppl):Abstract nr POSTER-THER-1409.