Methodist Hospital

OBJECTIVE: To provide an update to the original Surviving Sepsis Campaign clinical management guidelines, "Surviving Sepsis Campaign guidelines for management of severe sepsis and septic shock," published in 2004. DESIGN: Modified Delphi method with a consensus conference of 55 international experts, several subsequent meetings of subgroups and key individuals, teleconferences, and electronic-based discussion among subgroups and among the entire committee. This process was conducted independently of any industry funding. METHODS: We used the GRADE system to guide assessment of quality of evidence from high (A) to very low (D) and to determine the strength of recommendations. A strong recommendation indicates that an intervention's desirable effects clearly outweigh its undesirable effects (risk, burden, cost), or clearly do not. Weak recommendations indicate that the tradeoff between desirable and undesirable effects is less clear. The grade of strong or weak is considered of greater clinical importance than a difference in letter level of quality of evidence. In areas without complete agreement, a formal process of resolution was developed and applied. Recommendations are grouped into those directly targeting severe sepsis, recommendations targeting general care of the critically ill patient that are considered high priority in severe sepsis, and pediatric considerations. RESULTS: Key recommendations, listed by category, include: early goal-directed resuscitation of the septic patient during the first 6 hrs after recognition (1C); blood cultures prior to antibiotic therapy (1C); imaging studies performed promptly to confirm potential source of infection (1C); administration of broad-spectrum antibiotic therapy within 1 hr of diagnosis of septic shock (1B) and severe sepsis without septic shock (1D); reassessment of antibiotic therapy with microbiology and clinical data to narrow coverage, when appropriate (1C); a usual 7-10 days of antibiotic therapy guided by clinical response (1D); source control with attention to the balance of risks and benefits of the chosen method (1C); administration of either crystalloid or colloid fluid resuscitation (1B); fluid challenge to restore mean circulating filling pressure (1C); reduction in rate of fluid administration with rising filing pressures and no improvement in tissue perfusion (1D); vasopressor preference for norepinephrine or dopamine to maintain an initial target of mean arterial pressure > or = 65 mm Hg (1C); dobutamine inotropic therapy when cardiac output remains low despite fluid resuscitation and combined inotropic/vasopressor therapy (1C); stress-dose steroid therapy given only in septic shock after blood pressure is identified to be poorly responsive to fluid and vasopressor therapy (2C); recombinant activated protein C in patients with severe sepsis and clinical assessment of high risk for death (2B except 2C for post-operative patients). In the absence of tissue hypoperfusion, coronary artery disease, or acute hemorrhage, target a hemoglobin of 7-9 g/dL (1B); a low tidal volume (1B) and limitation of inspiratory plateau pressure strategy (1C) for acute lung injury (ALI)/acute respiratory distress syndrome (ARDS); application of at least a minimal amount of positive end-expiratory pressure in acute lung injury (1C); head of bed elevation in mechanically ventilated patients unless contraindicated (1B); avoiding routine use of pulmonary artery catheters in ALI/ARDS (1A); to decrease days of mechanical ventilation and ICU length of stay, a conservative fluid strategy for patients with established ALI/ARDS who are not in shock (1C); protocols for weaning and sedation/analgesia (1B); using either intermittent bolus sedation or continuous infusion sedation with daily interruptions or lightening (1B); avoidance of neuromuscular blockers, if at all possible (1B); institution of glycemic control (1B) targeting a blood glucose < 150 mg/dL after initial stabilization ( 2C ); equivalency of continuous veno-veno hemofiltration or intermittent hemodialysis (2B); prophylaxis for deep vein thrombosis (1A); use of stress ulcer prophylaxis to prevent upper GI bleeding using H2 blockers (1A) or proton pump inhibitors (1B); and consideration of limitation of support where appropriate (1D). Recommendations specific to pediatric severe sepsis include: greater use of physical examination therapeutic end points (2C); dopamine as the first drug of choice for hypotension (2C); steroids only in children with suspected or proven adrenal insufficiency (2C); a recommendation against the use of recombinant activated protein C in children (1B). CONCLUSION: There was strong agreement among a large cohort of international experts regarding many level 1 recommendations for the best current care of patients with severe sepsis. Evidenced-based recommendations regarding the acute management of sepsis and septic shock are the first step toward improved outcomes for this important group of critically ill patients.

OBJECTIVE: To provide an update to "Surviving Sepsis Campaign Guidelines for Management of Sepsis and Septic Shock: 2012." DESIGN: A consensus committee of 55 international experts representing 25 international organizations was convened. Nominal groups were assembled at key international meetings (for those committee members attending the conference). A formal conflict-of-interest (COI) policy was developed at the onset of the process and enforced throughout. A stand-alone meeting was held for all panel members in December 2015. Teleconferences and electronic-based discussion among subgroups and among the entire committee served as an integral part of the development. METHODS: The panel consisted of five sections: hemodynamics, infection, adjunctive therapies, metabolic, and ventilation. Population, intervention, comparison, and outcomes (PICO) questions were reviewed and updated as needed, and evidence profiles were generated. Each subgroup generated a list of questions, searched for best available evidence, and then followed the principles of the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) system to assess the quality of evidence from high to very low, and to formulate recommendations as strong or weak, or best practice statement when applicable. RESULTS: The Surviving Sepsis Guideline panel provided 93 statements on early management and resuscitation of patients with sepsis or septic shock. Overall, 32 were strong recommendations, 39 were weak recommendations, and 18 were best-practice statements. No recommendation was provided for four questions. CONCLUSIONS: Substantial agreement exists among a large cohort of international experts regarding many strong recommendations for the best care of patients with sepsis. Although a significant number of aspects of care have relatively weak support, evidence-based recommendations regarding the acute management of sepsis and septic shock are the foundation of improved outcomes for these critically ill patients with high mortality.

BACKGROUND: We compared ranibizumab--a recombinant, humanized, monoclonal antibody Fab that neutralizes all active forms of vascular endothelial growth factor A--with photodynamic therapy with verteporfin in the treatment of predominantly classic neovascular age-related macular degeneration. METHODS: During the first year of this 2-year, multicenter, double-blind study, we randomly assigned patients in a 1:1:1 ratio to receive monthly intravitreal injections of ranibizumab (0.3 mg or 0.5 mg) plus sham verteporfin therapy or monthly sham injections plus active verteporfin therapy. The primary end point was the proportion of patients losing fewer than 15 letters from baseline visual acuity at 12 months. RESULTS: Of the 423 patients enrolled, 94.3% of those given 0.3 mg of ranibizumab and 96.4% of those given 0.5 mg lost fewer than 15 letters, as compared with 64.3% of those in the verteporfin group (P<0.001 for each comparison). Visual acuity improved by 15 letters or more in 35.7% of the 0.3-mg group and 40.3% of the 0.5-mg group, as compared with 5.6% of the verteporfin group (P<0.001 for each comparison). Mean visual acuity increased by 8.5 letters in the 0.3-mg group and 11.3 letters in the 0.5-mg group, as compared with a decrease of 9.5 letters in the verteporfin group (P<0.001 for each comparison). Among 140 patients treated with 0.5 mg of ranibizumab, presumed endophthalmitis occurred in 2 patients (1.4%) and serious uveitis in 1 (0.7%). CONCLUSIONS: Ranibizumab was superior to verteporfin as intravitreal treatment of predominantly classic neovascular age-related macular degeneration, with low rates of serious ocular adverse events. Treatment improved visual acuity on average at 1 year. (ClinicalTrials.gov number, NCT00061594 [ClinicalTrials.gov].).

BACKGROUND: Student mental health in higher education has been an increasing concern. The COVID-19 pandemic situation has brought this vulnerable population into renewed focus. OBJECTIVE: Our study aims to conduct a timely assessment of the effects of the COVID-19 pandemic on the mental health of college students. METHODS: We conducted interview surveys with 195 students at a large public university in the United States to understand the effects of the pandemic on their mental health and well-being. The data were analyzed through quantitative and qualitative methods. RESULTS: Of the 195 students, 138 (71%) indicated increased stress and anxiety due to the COVID-19 outbreak. Multiple stressors were identified that contributed to the increased levels of stress, anxiety, and depressive thoughts among students. These included fear and worry about their own health and of their loved ones (177/195, 91% reported negative impacts of the pandemic), difficulty in concentrating (173/195, 89%), disruptions to sleeping patterns (168/195, 86%), decreased social interactions due to physical distancing (167/195, 86%), and increased concerns on academic performance (159/195, 82%). To cope with stress and anxiety, participants have sought support from others and helped themselves by adopting either negative or positive coping mechanisms. CONCLUSIONS: Due to the long-lasting pandemic situation and onerous measures such as lockdown and stay-at-home orders, the COVID-19 pandemic brings negative impacts on higher education. The findings of our study highlight the urgent need to develop interventions and preventive strategies to address the mental health of college students.

autophagic responses. Here, we critically discuss current methods of assessing autophagy and the information they can, or cannot, provide. Our ultimate goal is to encourage intellectual and technical innovation in the field.

Abstract In 2019, the International Scientific Association for Probiotics and Prebiotics (ISAPP) convened a panel of experts specializing in nutrition, microbial physiology, gastroenterology, paediatrics, food science and microbiology to review the definition and scope of postbiotics. The term ‘postbiotics’ is increasingly found in the scientific literature and on commercial products, yet is inconsistently used and lacks a clear definition. The purpose of this panel was to consider the scientific, commercial and regulatory parameters encompassing this emerging term, propose a useful definition and thereby establish a foundation for future developments. The panel defined a postbiotic as a “preparation of inanimate microorganisms and/or their components that confers a health benefit on the host”. Effective postbiotics must contain inactivated microbial cells or cell components, with or without metabolites, that contribute to observed health benefits. The panel also discussed existing evidence of health-promoting effects of postbiotics, potential mechanisms of action, levels of evidence required to meet the stated definition, safety and implications for stakeholders. The panel determined that a definition of postbiotics is useful so that scientists, clinical triallists, industry, regulators and consumers have common ground for future activity in this area. A generally accepted definition will hopefully lead to regulatory clarity and promote innovation and the development of new postbiotic products.

NF-κB pathway consists of canonical and non-canonical pathways. The canonical NF-κB is activated by various stimuli, transducing a quick but transient transcriptional activity, to regulate the expression of various proinflammatory genes and also serve as the critical mediator for inflammatory response. Meanwhile, the activation of the non-canonical NF-κB pathway occurs through a handful of TNF receptor superfamily members. Since the activation of this pathway involves protein synthesis, the kinetics of non-canonical NF-κB activation is slow but persistent, in concordance with its biological functions in the development of immune cell and lymphoid organ, immune homeostasis and immune response. The activation of the canonical and non-canonical NF-κB pathway is tightly controlled, highlighting the vital roles of ubiquitination in these pathways. Emerging studies indicate that dysregulated NF-κB activity causes inflammation-related diseases as well as cancers, and NF-κB has been long proposed as the potential target for therapy of diseases. This review attempts to summarize our current knowledge and updates on the mechanisms of NF-κB pathway regulation and the potential therapeutic application of inhibition of NF-κB signaling in cancer and inflammatory diseases.

BACKGROUND: Atherosclerotic intracranial arterial stenosis is an important cause of stroke that is increasingly being treated with percutaneous transluminal angioplasty and stenting (PTAS) to prevent recurrent stroke. However, PTAS has not been compared with medical management in a randomized trial. METHODS: We randomly assigned patients who had a recent transient ischemic attack or stroke attributed to stenosis of 70 to 99% of the diameter of a major intracranial artery to aggressive medical management alone or aggressive medical management plus PTAS with the use of the Wingspan stent system. The primary end point was stroke or death within 30 days after enrollment or after a revascularization procedure for the qualifying lesion during the follow-up period or stroke in the territory of the qualifying artery beyond 30 days. RESULTS: Enrollment was stopped after 451 patients underwent randomization, because the 30-day rate of stroke or death was 14.7% in the PTAS group (nonfatal stroke, 12.5%; fatal stroke, 2.2%) and 5.8% in the medical-management group (nonfatal stroke, 5.3%; non-stroke-related death, 0.4%) (P=0.002). Beyond 30 days, stroke in the same territory occurred in 13 patients in each group. Currently, the mean duration of follow-up, which is ongoing, is 11.9 months. The probability of the occurrence of a primary end-point event over time differed significantly between the two treatment groups (P=0.009), with 1-year rates of the primary end point of 20.0% in the PTAS group and 12.2% in the medical-management group. CONCLUSIONS: In patients with intracranial arterial stenosis, aggressive medical management was superior to PTAS with the use of the Wingspan stent system, both because the risk of early stroke after PTAS was high and because the risk of stroke with aggressive medical therapy alone was lower than expected. (Funded by the National Institute of Neurological Disorders and Stroke and others; SAMMPRIS ClinicalTrials.gov number, NCT00576693.).

Mutations in the gene encoding the transcriptional repressor methyl-CpG binding protein 2 (MeCP2) cause the neurodevelopmental disorder Rett syndrome. Loss of function as well as increased dosage of the MECP2 gene cause a host of neuropsychiatric disorders. To explore the molecular mechanism(s) underlying these disorders, we examined gene expression patterns in the hypothalamus of mice that either lack or overexpress MeCP2. In both models, MeCP2 dysfunction induced changes in the expression levels of thousands of genes, but unexpectedly the majority of genes (approximately 85%) appeared to be activated by MeCP2. We selected six genes and confirmed that MeCP2 binds to their promoters. Furthermore, we showed that MeCP2 associates with the transcriptional activator CREB1 at the promoter of an activated target but not a repressed target. These studies suggest that MeCP2 regulates the expression of a wide range of genes in the hypothalamus and that it can function as both an activator and a repressor of transcription.

BACKGROUND: Stroke-associated pneumonia (SAP) has been implicated in the morbidity, mortality and increased medical cost after acute ischemic stroke. The annual cost of SAP during hospitalization in the United States approaches USD 459 million. The incidence and prognosis of SAP among intensive care unit (ICU) patients have not been thoroughly investigated. We reviewed the pathophysiology, microbiology, incidence, risk factors, outcomes and prophylaxis of SAP with special attention to ICU studies. METHODS: To determine the incidence, risk factors and prognosis of acute SAP, PubMed was searched using the terms 'pneumonia' AND 'neurology intensive unit' and the MeSH terms 'stroke' AND 'pneumonia'. Non-English literature, case reports and chronic SAP studies were excluded. Studies were classified into 5 categories according to the setting they were performed in: neurological intensive care units (NICUs), medical intensive care units (MICUs), stroke units, mixed studies combining more than one setting or when the settings were not specified and rehabilitation studies. RESULTS: The incidences of SAP in the following settings were: NICUs 4.1-56.6%, MICUs 17-50%, stroke units 3.9-44%, mixed studies 3.9-23.8% and rehabilitation 3.2-11%. The majority of NICU and MICU studies were heterogeneous including different neurovascular diseases, which partly explains the wide range of SAP incidence. The higher incidence in the majority of ICU studies compared to stroke units or acute floor studies is likely explained by the presence of mechanical ventilation, higher stroke severity causing higher rates of aspiration and stroke-induced immunodepression among ICU patients. The short-term mortality of SAP was increased among the mixed and stroke unit studies ranging between 10.1 and 37.3%. SAP was associated with worse functional outcome in the majority of stroke unit and floor studies. Mortality was less consistent among NICU and MICU studies. This difference could be due to the heterogeneity of ICU studies and the effect of small sample size or other independent risk factors for mortality such as the larger neurological deficit, mechanical ventilation, and age, which may simultaneously increase the risk of SAP and mortality confounding the outcomes of SAP itself. The pathophysiology of SAP is likely explained by aspiration combined with stroke-induced immunodepression through complex humeral and neural pathways that include the hypothalamic-pituitary-adrenal axis, parasympathetic and sympathetic systems. CONCLUSIONS: A unified definition of SAP, strict inclusion criteria, and the presence of a long-term follow-up need to be applied to the future prospective studies to better identify the incidence and prognosis of SAP, especially among ICU patients.

BACKGROUND: The accuracy of multidetector computed tomographic angiography (CTA) for the diagnosis of acute pulmonary embolism has not been determined conclusively. METHODS: The Prospective Investigation of Pulmonary Embolism Diagnosis II trial was a prospective, multicenter investigation of the accuracy of multidetector CTA alone and combined with venous-phase imaging (CTA-CTV) for the diagnosis of acute pulmonary embolism. We used a composite reference test to confirm or rule out the diagnosis of pulmonary embolism. RESULTS: Among 824 patients with a reference diagnosis and a completed CT study, CTA was inconclusive in 51 because of poor image quality. Excluding such inconclusive studies, the sensitivity of CTA was 83 percent and the specificity was 96 percent. Positive predictive values were 96 percent with a concordantly high or low probability on clinical assessment, 92 percent with an intermediate probability on clinical assessment, and nondiagnostic if clinical probability was discordant. CTA-CTV was inconclusive in 87 of 824 patients because the image quality of either CTA or CTV was poor. The sensitivity of CTA-CTV for pulmonary embolism was 90 percent, and specificity was 95 percent. CTA-CTV was also nondiagnostic with a discordant clinical probability. CONCLUSIONS: In patients with suspected pulmonary embolism, multidetector CTA-CTV has a higher diagnostic sensitivity than does CTA alone, with similar specificity. The predictive value of either CTA or CTA-CTV is high with a concordant clinical assessment, but additional testing is necessary when the clinical probability is inconsistent with the imaging results.

BACKGROUND: Evidence suggests that the COVID-19 pandemic has generally increased levels of stress and depression among the public. However, the impact on college students in the United States has not been well-documented. OBJECTIVE: This paper surveys the mental health status and severity of depression and anxiety of college students in a large university system in the United States during the COVID-19 pandemic. METHODS: An online survey was conducted among undergraduate and graduate students recruited from Texas A&M University via email. The survey consisted of two standardized scales-the Patient Health Questionnaire-9 and the General Anxiety Disorder-7-for depression and anxiety, and additional multiple-choice and open-ended questions regarding stressors and coping mechanisms specific to COVID-19. RESULTS: Among the 2031 participants, 48.14% (n=960) showed a moderate-to-severe level of depression, 38.48% (n=775) showed a moderate-to-severe level of anxiety, and 18.04% (n=366) had suicidal thoughts. A majority of participants (n=1443, 71.26%) indicated that their stress/anxiety levels had increased during the pandemic. Less than half of the participants (n=882, 43.25%) indicated that they were able to cope adequately with the stress related to the current situation. CONCLUSIONS: The proportion of respondents showing depression, anxiety, and/or suicidal thoughts is alarming. Respondents reported academic-, health-, and lifestyle-related concerns caused by the pandemic. Given the unexpected length and severity of the outbreak, these concerns need to be further understood and addressed.

PURPOSE: Genomic profiling studies suggest that triple-negative breast cancer (TNBC) is a heterogeneous disease. In this study, we sought to define TNBC subtypes and identify subtype-specific markers and targets. EXPERIMENTAL DESIGN: RNA and DNA profiling analyses were conducted on 198 TNBC tumors [estrogen receptor (ER) negativity defined as Allred scale value ≤ 2] with >50% cellularity (discovery set: n = 84; validation set: n = 114) collected at Baylor College of Medicine (Houston, TX). An external dataset of seven publically accessible TNBC studies was used to confirm results. DNA copy number, disease-free survival (DFS), and disease-specific survival (DSS) were analyzed independently using these datasets. RESULTS: We identified and confirmed four distinct TNBC subtypes: (i) luminal androgen receptor (AR; LAR), (ii) mesenchymal (MES), (iii) basal-like immunosuppressed (BLIS), and (iv) basal-like immune-activated (BLIA). Of these, prognosis is worst for BLIS tumors and best for BLIA tumors for both DFS (log-rank test: P = 0.042 and 0.041, respectively) and DSS (log-rank test: P = 0.039 and 0.029, respectively). DNA copy number analysis produced two major groups (LAR and MES/BLIS/BLIA) and suggested that gene amplification drives gene expression in some cases [FGFR2 (BLIS)]. Putative subtype-specific targets were identified: (i) LAR: androgen receptor and the cell surface mucin MUC1, (ii) MES: growth factor receptors [platelet-derived growth factor (PDGF) receptor A; c-Kit], (iii) BLIS: an immunosuppressing molecule (VTCN1), and (iv) BLIA: Stat signal transduction molecules and cytokines. CONCLUSION: There are four stable TNBC subtypes characterized by the expression of distinct molecular profiles that have distinct prognoses. These studies identify novel subtype-specific targets that can be targeted in the future for the effective treatment of TNBCs.

A subset of stem cells, termed the "side population" (SP), has been identified in several tissues in mammalian species. These cells maintain a high efflux capability for antimitotic drugs. We have investigated whether functionally equivalent stem cells also may be detected in human cancers. We initially examined primary tumor cells from 23 patients with neuroblastoma and cell lines derived from a range of other tumors. A distinct SP was found in neuroblastoma cells from 15 of 23 patients (65%). The SP was capable of sustained expansion ex vivo and showed evidence for asymmetric division, generating both SP and non-SP progeny. These cells also expressed high levels of ABCG2 and ABCA3 transporter genes and had a greater capacity to expel cytotoxic drugs, such as mitoxantrone, resulting in better survival. A SP also was detected in breast cancer, lung cancer, and glioblastoma cell lines, suggesting that this phenotype defines a class of cancer stem cells with inherently high resistance to chemotherapeutic agents that should be targeted during the treatment of malignant disease.

BACKGROUND: Few published studies have combined clinical prognostic factors into risk profiles that can be used to predict the likelihood of recurrence or metastatic progression in patients following treatment of prostate cancer. We developed a nomogram that allows prediction of disease recurrence through use of preoperative clinical factors for patients with clinically localized prostate cancer who are candidates for treatment with a radical prostatectomy. METHODS: By use of Cox proportional hazards regression analysis, we modeled the clinical data and disease follow-up for 983 men with clinically localized prostate cancer whom we intended to treat with a radical prostatectomy. Clinical data included pretreatment serum prostate-specific antigen levels, biopsy Gleason scores, and clinical stage. Treatment failure was recorded when there was clinical evidence of disease recurrence, a rising serum prostate-specific antigen level (two measurements of 0.4 ng/mL or greater and rising), or initiation of adjuvant therapy. Validation was performed on a separate sample of 168 men, also from our institution. RESULTS: Treatment failure (i.e., cancer recurrence) was noted in 196 of the 983 men, and the patients without failure had a median follow-up of 30 months (range, 1-146 months). The 5-year probability of freedom from failure for the cohort was 73% (95% confidence interval = 69%-76%). The predictions from the nomogram appeared accurate and discriminating, with a validation sample area under the receiver operating characteristic curve (i.e., comparison of the predicted probability with the actual outcome) of 0.79. CONCLUSIONS: A nomogram has been developed that can be used to predict the 5-year probability of treatment failure among men with clinically localized prostate cancer treated with radical prostatectomy.

BACKGROUND: In two interim analyses of this trial, patients with advanced heart failure who were treated with a fully magnetically levitated centrifugal-flow left ventricular assist device were less likely to have pump thrombosis or nondisabling stroke than were patients treated with a mechanical-bearing axial-flow left ventricular assist device. METHODS: We randomly assigned patients with advanced heart failure to receive either the centrifugal-flow pump or the axial-flow pump irrespective of the intended goal of use (bridge to transplantation or destination therapy). The composite primary end point was survival at 2 years free of disabling stroke or reoperation to replace or remove a malfunctioning device. The principal secondary end point was pump replacement at 2 years. RESULTS: This final analysis included 1028 enrolled patients: 516 in the centrifugal-flow pump group and 512 in the axial-flow pump group. In the analysis of the primary end point, 397 patients (76.9%) in the centrifugal-flow pump group, as compared with 332 (64.8%) in the axial-flow pump group, remained alive and free of disabling stroke or reoperation to replace or remove a malfunctioning device at 2 years (relative risk, 0.84; 95% confidence interval [CI], 0.78 to 0.91; P<0.001 for superiority). Pump replacement was less common in the centrifugal-flow pump group than in the axial-flow pump group (12 patients [2.3%] vs. 57 patients [11.3%]; relative risk, 0.21; 95% CI, 0.11 to 0.38; P<0.001). The numbers of events per patient-year for stroke of any severity, major bleeding, and gastrointestinal hemorrhage were lower in the centrifugal-flow pump group than in the axial-flow pump group. CONCLUSIONS: Among patients with advanced heart failure, a fully magnetically levitated centrifugal-flow left ventricular assist device was associated with less frequent need for pump replacement than an axial-flow device and was superior with respect to survival free of disabling stroke or reoperation to replace or remove a malfunctioning device. (Funded by Abbott; MOMENTUM 3 ClinicalTrials.gov number, NCT02224755.).

IMPORTANCE: Glioblastoma is the most devastating primary malignancy of the central nervous system in adults. Most patients die within 1 to 2 years of diagnosis. Tumor-treating fields (TTFields) are a locoregionally delivered antimitotic treatment that interferes with cell division and organelle assembly. OBJECTIVE: To evaluate the efficacy and safety of TTFields used in combination with temozolomide maintenance treatment after chemoradiation therapy for patients with glioblastoma. DESIGN, SETTING, AND PARTICIPANTS: After completion of chemoradiotherapy, patients with glioblastoma were randomized (2:1) to receive maintenance treatment with either TTFields plus temozolomide (n = 466) or temozolomide alone (n = 229) (median time from diagnosis to randomization, 3.8 months in both groups). The study enrolled 695 of the planned 700 patients between July 2009 and November 2014 at 83 centers in the United States, Canada, Europe, Israel, and South Korea. The trial was terminated based on the results of this planned interim analysis. INTERVENTIONS: Treatment with TTFields was delivered continuously (>18 hours/day) via 4 transducer arrays placed on the shaved scalp and connected to a portable medical device. Temozolomide (150-200 mg/m2/d) was given for 5 days of each 28-day cycle. MAIN OUTCOMES AND MEASURES: The primary end point was progression-free survival in the intent-to-treat population (significance threshold of .01) with overall survival in the per-protocol population (n = 280) as a powered secondary end point (significance threshold of .006). This prespecified interim analysis was to be conducted on the first 315 patients after at least 18 months of follow-up. RESULTS: The interim analysis included 210 patients randomized to TTFields plus temozolomide and 105 randomized to temozolomide alone, and was conducted at a median follow-up of 38 months (range, 18-60 months). Median progression-free survival in the intent-to-treat population was 7.1 months (95% CI, 5.9-8.2 months) in the TTFields plus temozolomide group and 4.0 months (95% CI, 3.3-5.2 months) in the temozolomide alone group (hazard ratio [HR], 0.62 [98.7% CI, 0.43-0.89]; P = .001). Median overall survival in the per-protocol population was 20.5 months (95% CI, 16.7-25.0 months) in the TTFields plus temozolomide group (n = 196) and 15.6 months (95% CI, 13.3-19.1 months) in the temozolomide alone group (n = 84) (HR, 0.64 [99.4% CI, 0.42-0.98]; P = .004). CONCLUSIONS AND RELEVANCE: In this interim analysis of 315 patients with glioblastoma who had completed standard chemoradiation therapy, adding TTFields to maintenance temozolomide chemotherapy significantly prolonged progression-free and overall survival. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00916409.

Hepatocellular carcinoma (HCC) is the most common primary liver malignancy and is a leading cause of cancer-related death worldwide. In the United States, HCC is the ninth leading cause of cancer deaths. Despite advances in prevention techniques, screening, and new technologies in both diagnosis and treatment, incidence and mortality continue to rise. Cirrhosis remains the most important risk factor for the development of HCC regardless of etiology. Hepatitis B and C are independent risk factors for the development of cirrhosis. Alcohol consumption remains an important additional risk factor in the United States as alcohol abuse is five times higher than hepatitis C. Diagnosis is confirmed without pathologic confirmation. Screening includes both radiologic tests, such as ultrasound, computerized tomography, and magnetic resonance imaging, and serological markers such as α-fetoprotein at 6-month intervals. Multiple treatment modalities exist; however, only orthotopic liver transplantation (OLT) or surgical resection is curative. OLT is available for patients who meet or are downstaged into the Milan or University of San Francisco criteria. Additional treatment modalities include transarterial chemoembolization, radiofrequency ablation, microwave ablation, percutaneous ethanol injection, cryoablation, radiation therapy, systemic chemotherapy, and molecularly targeted therapies. Selection of a treatment modality is based on tumor size, location, extrahepatic spread, and underlying liver function. HCC is an aggressive cancer that occurs in the setting of cirrhosis and commonly presents in advanced stages. HCC can be prevented if there are appropriate measures taken, including hepatitis B virus vaccination, universal screening of blood products, use of safe injection practices, treatment and education of alcoholics and intravenous drug users, and initiation of antiviral therapy. Continued improvement in both surgical and nonsurgical approaches has demonstrated significant benefits in overall survival. While OLT remains the only curative surgical procedure, the shortage of available organs precludes this therapy for many patients with HCC.

BACKGROUND: The prognosis of patients hospitalized with acute myocardial ischemia is quite variable. We examined the value of serum levels of cardiac troponin T, serum creatine kinase MB (CK-MB) levels, and electrocardiographic abnormalities for risk stratification in patients with acute myocardial ischemia. METHODS: We studied 855 patients within 12 hours of the onset of symptoms. Cardiac troponin T levels, CK-MB levels, and electrocardiograms were analyzed in a blinded fashion at the core laboratory. We used logistic regression to assess the usefulness of baseline levels of cardiac troponin T and CK-MB and the electrocardiographic category assigned at admission-ST-segment elevation, ST-segment depression, T-wave inversion, or the presence of confounding factors that impair the detection of ischemia (bundle-branch block and paced rhythms)-in predicting outcome. RESULTS: On admission, 289 of 801 patients with base-line serum samples had elevated troponin T levels (> 0.1 ng per milliliter). Mortality within 30 days was significantly higher in these patients than in patients with lower levels of troponin T (11.8 percent vs. 3.9 percent, P < 0.001). The troponin T level was the variable most strongly related to 30-day mortality (chi-square = 21, P < 0.001), followed by the electrocardiographic category (chi-square = 14, P = 0.003) and the CK-MB level (chi-square = 11, P = 0.004). Troponin T levels remained significantly predictive of 30-day mortality in a model that contained the electrocardiographic categories and CK-MB levels (chi-square = 9.2, P = 0.027). CONCLUSIONS: The cardiac troponin T level is a powerful, independent risk marker in patients who present with acute myocardial ischemia. It allows further stratification of risk when combined with standard measures such as electrocardiography and the CK-MB level.

Echocardiographic imaging is ideally suited for the evaluation of cardiac mechanics because of its intrinsically dynamic nature. Because for decades, echocardiography has been the only imaging modality that allows dynamic imaging of the heart, it is only natural that new, increasingly automated techniques for sophisticated analysis of cardiac mechanics have been driven by researchers and manufacturers of ultrasound imaging equipment. Several such techniques have emerged over the past decades to address the issue of reader's experience and inter-measurement variability in interpretation. Some were widely embraced by echocardiographers around the world and became part of the clinical routine, whereas others remained limited to research and exploration of new clinical applications. Two such techniques have dominated the research arena of echocardiography: (1) Doppler-based tissue velocity measurements, frequently referred to as tissue Doppler or myocardial Doppler, and (2) speckle tracking on the basis of displacement measurements. Both types of measurements lend themselves to the derivation of multiple parameters of myocardial function. The goal of this document is to focus on the currently available techniques that allow quantitative assessment of myocardial function via image-based analysis of local myocardial dynamics, including Doppler tissue imaging and speckle-tracking echocardiography, as well as integrated back- scatter analysis. This document describes the current and potential clinical applications of these techniques and their strengths and weaknesses, briefly surveys a selection of the relevant published literature while highlighting normal and abnormal findings in the context of different cardiovascular pathologies, and summarizes the unresolved issues, future research priorities, and recommended indications for clinical use.