Search

XLSX file - 66K, List of the differentially expressed probes for the analysis Epithelioid MPM vs. Sarcomatoid MPM.

XLSX file - 196K, List of the enriched functional terms for the analysis Epithelioid MPM vs. Sarcomatoid MPM.

XLSX file - 240K, List of the differentially expressed probes for the analysis MPM vs. other tumor types.

XLSX file - 31K, PCR primers and genes. Sequences of the primers for the differential diagnosis of MPM. Selected genes for each diagnostic test.

XLSX file - 191K, Results of the binary diagnostic tests using microarray data and RT-PCR data in the original set of samples.

XLSX file - 34K, List of the enriched functional terms for for the analysis MPM vs. other tumor types.

XLSX file - 42K, Results of the binary diagnostic tests in a test set analyzed by RT-PCR.

PDF file - 53K, Identification of Diagnostic Molecular Markers and Data Analysis, Real-Time Quantitative PCR Results, Hierarchical clustering analysis.

PDF file - 188K, Heat-map of the 26-gene signature used in the sequential combination of gene expression ratio tests in the 112 thoracic samples. Probes are annotated with gene symbol on the right. Relative gene expression levels are given by the scale at the top. The red asterisk indicates the mesothelioma samples.

Purpose: To develop a standardized approach for molecular diagnostics, we used the gene expression ratio bioinformatic technique to design a molecular signature to diagnose malignant pleural mesothelioma (MPM) from among other potentially confounding diagnoses and differentiate the epithelioid from the sarcomatoid histologic subtype of MPM. In addition, we searched for pathways relevant in MPM in comparison with other related cancers to identify unique molecular features in MPM.Experimental Design: We conducted microarray analysis on 113 specimens including MPMs and a spectrum of tumors and benign tissues comprising the differential diagnosis of MPM. We generated a sequential combination of binary gene expression ratio tests able to discriminate MPM from other thoracic malignancies. We compared this method with other bioinformatic tools and validated this signature in an independent set of 170 samples. Functional enrichment analysis was conducted to identify differentially expressed probes.Results: A sequential combination of gene expression ratio tests was the best molecular approach to distinguish MPM from all the other samples. Bioinformatic and molecular validations showed that the sequential gene ratio tests were able to identify the MPM samples with high sensitivity and specificity. In addition, the gene ratio technique was able to differentiate the epithelioid from the sarcomatoid type of MPM. Novel genes and pathways specifically activated in MPM were identified.Conclusions: New clinically relevant molecular tests have been generated using a small number of genes to accurately distinguish MPMs from other thoracic samples, supporting our hypothesis that the gene expression ratio approach could be a useful tool in the differential diagnosis of cancers. Clin Cancer Res; 19(9); 2493–502. ©2013 AACR.

This review describes the management of mechanical ventilation in patients with acute respiratory distress syndrome, including in those with coronavirus disease 2019. Low tidal volume ventilation with a moderate to high positive end-expiratory pressure remains the foundation of an evidence-based approach. We consider strategies for setting positive end-expiratory pressure levels, the use of recruitment maneuvers, and the potential role of driving pressure. Rescue therapies including prone positioning and extracorporeal membrane oxygenation are also discussed.

IntroductionThe COVID-19 pandemic brought an urgent need to discover novel effective therapeutics for patients hospitalized with severe COVID-19. The ISPY COVID trial was designed and implemented in early 2020 to evaluate investigational agents rapidly and simultaneously on a phase 2 adaptive platform. This manuscript outlines the design, rationale, implementation, and challenges of the ISPY COVID trial during the first phase of trial activity from April 2020 until December 2021.Methods and analysisThe ISPY COVID Trial is a multi-center open label phase 2 platform trial in the United States designed to evaluate therapeutics that may have a large effect on improving outcomes from severe COVID-19. The ISPY COVID Trial network includes academic and community hospitals with significant geographic diversity across the country. Enrolled patients are randomized to receive one of up to four investigational agents or a control and are evaluated for a family of two primary outcomes—time to recovery and mortality. The statistical design uses a Bayesian model with “stopping” and “graduation” criteria designed to efficiently discard ineffective therapies and graduate promising agents for definitive efficacy trials. Each investigational agent arm enrolls to a maximum of 125 patients per arm and is compared to concurrent controls. As of December 2021, 11 investigational agent arms had been activated, and 8 arms were complete. Enrollment and adaptation of the trial design is ongoing.Ethics and disseminationISPY COVID operates under a central institutional review board via Wake Forest School of Medicine IRB00066805. Data generated from this trial will be reported in peer reviewed medical journals.Trial registration numberClinicaltrials.gov registration number NCT04488081Strengths and limitations of this studyThe ISPY COVID Trial was developed in early 2020 to rapidly and simultaneously evaluate therapeutics for severe COVID-19 on an adaptive open label phase 2 platformThe ISPY COVID Adaptive Platform Trial Network is an academic-industry partnership that includes academic and community hospitals spanning a wide geographic area across the United StatesOf December 2021, 11 investigational agent arms have been activated on the ISPY COVID Trial PlatformThe ISPY COVID Trial was designed to identify therapeutic agents with a large clinical effect for further testing in definitive efficacy trials—limitations to this approach include the risk of a type 2 error

Simple Summary Sex differences in tumor incidence and mortality have been documented for many different cancer types. In malignant pleural mesothelioma, a deadly disease, many studies have shown that women not only develop this cancer less frequently than men, but those who do are likely to live longer after surgery. These differences have been postulated to reflect circulating estrogen levels and tumor expression of estrogen receptors that may influence tumor progression. We identified high expression of the RAS like estrogen regulated growth inhibitor gene (RERG), to correlate with longer survival after surgery among women. Survival in men was not associated with RERG expression. Additionally, we found no association between survival and tumor expression of estrogen receptor genes. Additional studies are needed to elucidate any role RERG may play in mesothelioma, and whether estrogen may be involved. Abstract Sex differences in incidence, prognosis, and treatment response have been described for many cancers. In malignant pleural mesothelioma (MPM), a lethal disease associated with asbestos exposure, men outnumber women 4 to 1, but women consistently live longer than men following surgery-based therapy. This study investigated whether tumor expression of genes associated with estrogen signaling could potentially explain observed survival differences. Two microarray datasets of MPM tumors were analyzed to discover estrogen-related genes associated with survival. A validation cohort of MPM tumors was selected to balance the numbers of men and women and control for competing prognostic influences. The RAS like estrogen regulated growth inhibitor (RERG) gene was identified as the most differentially-expressed estrogen-related gene in these tumors and predicted prognosis in discovery datasets. In the sex-matched validation cohort, low RERG expression was significantly associated with increased risk of death among women. No association between RERG expression and survival was found among men, and no relationship between estrogen receptor protein or gene expression and survival was found for either sex. Additional investigations are needed to elucidate the molecular mechanisms underlying this association and its sex specificity.

Sex differences in incidence, prognosis, and treatment response have been described for many cancers. In malignant pleural mesothelioma (MPM), a lethal disease associated with asbestos exposure, men outnumber women 4 to 1, but women consistently live longer than men following surgery-based therapy. This study investigated whether tumor expression of genes associated with estrogen signaling could potentially explain observed survival differences. Two microarray datasets of MPM tumors were analyzed to discover estrogen-related genes associated with survival. A validation cohort of MPM tumors was selected to balance the numbers of men and women and control for competing prognostic influences. The RAS like estrogen regulated growth inhibitor (RERG) gene was identified as the most differentially-expressed estrogen-related gene in these tumors and predicted prognosis in discovery datasets. In the sex-matched validation cohort, low RERG expression was significantly associated with increased risk of death among women. No association between RERG expression and survival was found among men, and no relationship between estrogen receptor protein or gene expression and survival was found for either sex. Additional investigations are needed to elucidate the molecular mechanisms underlying this association and its sex specificity. Published version

Despite the resurgence of early tourniquet use for control of exsanguinating limb hemorrhage in the military setting, its appropriate role in civilian emergency medical services (EMS) has been less clear.To describe the experience of prehospital tourniquet use in an urban, civilian EMS setting.A retrospective review of EMS prehospital care reports was performed from January 1, 2005 to December 1, 2012. Data, including the time duration of prehospital tourniquet placement, EMS scene time, mechanisms of injury, and patient demographics, underwent descriptive analysis. Outcomes data for participating receiving hospitals were also reviewed.Ninety-eight cases of prehospital tourniquet use were identified. The most common causes of injury were penetrating gunshot or stabbing wounds (67.4%, 66/98); 7.1% (7/98) of cases were due to blunt trauma; 23.5% (23/98) of cases were from nontraumatic hemorrhage related to uncontrolled hemodialysis shunt or wound bleeding; 45.4% (44/97) of cases were placed on a lower extremity; 54.6% (53/97) were placed on an upper extremity. Placement was successful in hemorrhage control in 91% (87/95, 95%CI: 85.9-97.3%) of cases. The average prehospital tourniquet placement time was 14.9 minutes. Half of all tourniquet placements were performed by basic life support providers. Hospital follow-up was available for 96.9% (95/98) of cases. Of these, the tourniquet was removed by EMS in 3.2% (3/95), the emergency department in 54.7% (52/95), or in the operating room (OR) in 31.6% (30/95) of the time; 46.7% (14/30) of these OR cases had a documented vascular injury needing repair. Ten deaths with hospital follow-up data were identified, none of which were due to tourniquet use. There was one case of forearm numbness potentially due to nerve injury and one case with potential vascular complication, representing an overall complication rate of 2.1% (2/95).The early use of tourniquets for extremity hemorrhage in an urban civilian EMS setting appears to be safe, with complications occurring infrequently.

Small-bowel obstruction secondary to internal hernia is a known postoperative complication of laparoscopic Roux-en-Y gastric bypass (RYGBP). Petersen's defect is the most common site of postoperative internal herniation. The authors describe their technique of closure of the infracolic component of the Petersen's defect using continuous non-absorbable suture material. The method has been used successfully to reduce the incidence of internal herniation after laparoscopic RYGBP.

Purpose: To develop a standardized approach for molecular diagnostics, we used the gene expression ratio bioinformatic technique to design a molecular signature to diagnose malignant pleural mesothelioma (MPM) from among other potentially confounding diagnoses and differentiate the epithelioid from the sarcomatoid histologic subtype of MPM. In addition, we searched for pathways relevant in MPM in comparison with other related cancers to identify unique molecular features in MPM. Experimental Design: We conducted microarray analysis on 113 specimens including MPMs and a spectrum of tumors and benign tissues comprising the differential diagnosis of MPM. We generated a sequential combination of binary gene expression ratio tests able to discriminate MPM from other thoracic malignancies. We compared this method with other bioinformatic tools and validated this signature in an independent set of 170 samples. Functional enrichment analysis was conducted to identify differentially expressed probes. Results: A sequential combination of gene expression ratio tests was the best molecular approach to distinguish MPM from all the other samples. Bioinformatic and molecular validations showed that the sequential gene ratio tests were able to identify the MPM samples with high sensitivity and specificity. In addition, the gene ratio technique was able to differentiate the epithelioid from the sarcomatoid type of MPM. Novel genes and pathways specifically activated in MPM were identified. Conclusions: New clinically relevant molecular tests have been generated using a small number of genes to accurately distinguish MPMs from other thoracic samples, supporting our hypothesis that the gene expression ratio approach could be a useful tool in the differential diagnosis of cancers. Clin Cancer Res; 19(9); 2493–502. ©2013 AACR.

Complete surgical resection is the main therapy for early-stage non-small cell lung cancer. Survival rates remain, at best, 80% for stage IA, necessitating the development of effective systemic therapy. Several large randomized control trials and meta-analyses provide evidence for the use of adjuvant chemotherapy for stage I to III, and are the basis for the standards of care. Cisplatin-based adjuvant chemotherapy regimens have shown 4% to 15% survival advantage at 5 years. Given this modest survival benefit, research is focused on the identification of prognostic and predictive markers to aid in the selection of appropriate adjuvant chemotherapy regimens.