Phase I trial of intravenous fenretinide (4-HPR) plus safingol in advanced malignancies.

PURPOSE: Fenretinide (4-HPR) is a synthetic retinoid that induces cytotoxicity through dihydroceramide production. Safingol, a stereochemical-variant dihydroceramide precursor, exhibits synergistic effects when administered with fenretinide in preclinical studies. We conducted a phase 1 dose-escalation clinical trial of this combination. METHODS: Fenretinide was administered as a 600 mg/m2 24-h infusion on Day 1 of a 21-day cycle followed by 900 mg/m2/day on Days 2 and 3. Safingol was concurrently administered as a 48-h infusion on Day 1 and 2 using 3 + 3 dose escalation. Primary endpoints were safety and maximum tolerated dose (MTD). Secondary endpoints included pharmacokinetics and efficacy. RESULTS: A total of 16 patients were enrolled (mean age 63 years, 50% female, median three prior lines of therapy), including 15 patients with refractory solid tumors and one with non-Hodgkin lymphoma. The median number of treatment cycles received was 2 (range 2-6). The most common adverse event (AE) was hypertriglyceridemia (88%; 38% ≥ Grade 3), attributed to the fenretinide intralipid infusion vehicle. Other treatment-related AEs occurring in ≥ 20% of patients included anemia, hypocalcemia, hypoalbuminemia, and hyponatremia. At safingol dose 420 mg/m2, one patient had a dose-limiting toxicity of grade 3 troponinemia and grade 4 myocarditis. Due to limited safingol supply, enrollment was halted at this dose level. Fenretinide and safingol pharmacokinetic profiles resembled those observed in monotherapy trials. Best radiographic response was stable disease (n = 2). CONCLUSION: Combination fenretinide plus safingol commonly causes hypertriglyceridemia and may be associated with cardiac events at higher safingol levels. Minimal activity in refractory solid tumors was observed. TRIAL REGISTRATION NUMBER: NCT01553071 (3.13.2012).

Real-World Burden of Nonalcoholic Steatohepatitis.

BACKGROUND & AIMS: Nonalcoholic steatohepatitis (NASH) is associated with an increase in healthcare resource use and poor health-related quality of life (HRQoL). We assessed the humanistic and economic burden of NASH, disease management, and patient journey. METHODS: We performed a cross-sectional analysis of data, collected from July through November 2017, from the Growth from Knowledge Disease Atlas Real-World Evidence program, reported by physicians in United States, France, and Germany. We extracted demographic and medical data from medical records. Some patients voluntarily completed a survey that provided information on disease history, treatment satisfaction, and patient-reported outcomes. RESULTS: We analyzed data from 1216 patients (mean age, 54.9±12.3 years; 57.5% male; mean body mass index, 31.7±6.9); 64.6% had biopsy-confirmed NASH and comorbidities were recorded for 41.3%. Treatments included lifestyle modification (64.6%) or use of statins (25.0%), vitamin E (23.5%), or metformin (20.2%). Patients with biopsy-confirmed NASH reported more physician (4.5 vs 3.7) and outpatient visits (1.8 vs1.4) than patients with suspected NASH not confirmed by biopsy. Among the 299 patients who completed the survey, 47.8% reported various symptoms associated to their NASH. Symptomatic patients reported significantly lower HRQoL than patients without symptoms. CONCLUSIONS: In an analysis of data from 3 countries, we found NASH to be associated with regular use of medical resources; patients with symptoms of NASH had reduced HRQoL. The burden of NASH appears to be underestimated. Studies are needed to determine the burden of NASH by fibrosis stage and disease severity.

Hospital incident command: First responders or receiving centers?

OBJECTIVES: (1) Propose a conceptual model of an alternative hospital incident management system (HIMS) that integrates concepts used by emergency operations centers (EOCs). (2) Compare HIMS to the standard hospital incident command system (HICS) model. DESIGN: A quasi-experimental study was performed. Two identical tabletop incident scenarios were presented, one utilizing HICS and one using HIMS. Participants completed postexercise surveys for each tabletop. Surveys contained both knowledge and satisfaction questions. The Likert Scale (1 strongly disagree and 5 strongly agree) was utilized for satisfaction questions. SETTING: The Medical University of South Carolina (MUSC), a level I trauma and academic center. PARTICIPANTS: N = 16; participants were members of MUSC's Emergency Management Committee. Participation was voluntary. MAIN OUTCOME MEASURES: (1) Knowledge of reporting structure within each model and (2) end-user satisfaction with model implementation. RESULTS: Using the HIMS model, participants correctly answered reporting structure questions 63.75 percent of the time in comparison to the HICS model of 35 percent (p value 0.001). Statistical analysis of qualitative satisfaction data between the two models revealed that HIMS was preferred over the HICS, 87.5 and 33.5 percent, respectively. CONCLUSIONS: The HIMs model is a new application for hospital incident management. This article serves to introduce the concept. Using the established EOC framework, continued research in this area is needed to validate the proposed HIMS model and standardize its design.

Effects of fluid resuscitation and dopamine on diaphragm performance, hydrogen peroxide, and apoptosis following hemorrhagic shock in a rat model.

The objective of this study was to determine the effectiveness of lactated Ringer's (LR) solution, sodium hydroxyethyl starch (hetastarch), and dopamine (DA) on diaphragm shortening (DS), diaphragm blood flow (DBF), diaphragm hydrogen peroxide (H2O2), and diaphragm apoptosis following hemorrhagic shock (HS). Sprague-Dawley rats were assigned to the following groups: HS, LR, LR plus DA, hetastarch, and hetastarch plus DA. After removing 40% of the blood volume, with exception of the HS group, an equal volume of resuscitation fluid was administered. The diaphragm was excised so that DBF, H2O2, and apoptosis could be measured. LR did not increase DBF and DS, whereas the other fluids increased DBF and DS. H2O2 and apoptosis decreased with LR administration. H2O2 and apoptosis were decreased to a much greater extent with LR plus DA, hetastarch, and hetastarch plus DA infusions. In conclusion, LR plus DA, hetastarch, and hetastarch plus DA maintained DS and DBF, which may be attributed to the decreases in reactive oxygen species as reflected by H2O2 and apoptosis.

Understanding the effects of oxygen administration in haemorrhagic shock.

AIMS AND OBJECTIVES: the aim of this article is to provide a review of the literature regarding oxygen administration and the use of oxygen in patients experiencing haemorrhagic shock (HS). RESULTS: oxygen is administered to patients to assist them in maintaining oxygenation. The administration of oxygen is complex and varies significantly among patients. In order to optimize patient care, clinicians need to be aware of the potential effects, both beneficial and harmful, that oxygen can have on the body. INCLUSION AND EXCLUSION CRITERIA: literature inclusion criteria for this article was any article (1995 to present) pertaining to oxygen administration and HS. Also included were articles related to tissue injury caused by an overabundance of free radicals with the administration of oxygen. Articles related to oxygen and wound healing, pollution, aerospace, food and industrial uses were excluded. CONCLUSIONS: this review of the literature provides an overview of the use of oxygen in clinical practice and HS. The harmful effects of oxygen are highlighted to alert the clinician to this potential when there is an overabundance of oxygen. RELEVANCE TO CLINICAL PRACTICE: oxygen is one of the most common drugs used in the medical community; however, the effects of oxygen on the body are not well understood. The use of oxygen if not prescribed correctly can cause cellular damage and death. Clinicians need to be more aware of the effects of oxygen and the damage it may cause if not administered properly.

Mitochondria: the hemi of the cell.

There are many organelles within a cell, each with individual responsibilities required for life. Of these organelles, the mitochondria are the hemi of the cell, producing the energy necessary for cell function. Reactive oxygen species can cause mitochondrial dysfunction and contribute to many diseases often seen in emergency departments. When reactive oxygen species are produced, the mitochondria undergo functional and structural changes causing the release of cytochrome c. Cytochrome c is responsible for activating apoptotic pathways leading to cell death. Apoptosis, or programmed cell death, is needed to maintain homeostasis in the body; however, when this occurs prematurely by an increase in reactive oxygen species production, many pathological conditions can occur. Clinicians in emergency departments caring for patients with different diseases should consider that the mitochondria may play an important role in patients' recovery. For instance, myocardial infarctions and burns are two examples of altered physiologic states that play a role in mitochondrial dysfunction. Awareness of the different treatments that target the mitochondria will prepare emergency department clinicians to better care for their patients.

Fluid resuscitation therapy for hemorrhagic shock.

Hemorrhagic shock is a severe life-threatening emergency affecting all organ systems of the body by depriving tissue of sufficient oxygen and nutrients by decreasing cardiac output. This article is a short review of the different types of shock, followed by information specifically referring to hemorrhagic shock. The American College of Surgeons categorized shock into 4 classes: (1) distributive; (2) obstructive; (3) cardiogenic; and (4) hemorrhagic. Similarly, the classes of hemorrhagic shock are grouped by signs and symptoms, amount of blood loss, and the type of fluid replacement. This updated review is helpful to trauma nurses in understanding the various clinical aspects of shock and the current recommendations for fluid resuscitation therapy following hemorrhagic shock.

Intra-renal resistance reflects warm ischaemic damage, and is further increased by static cold storage: a model of non-heart-beating donor kidneys.

BACKGROUND: Non-heart beating donor kidneys increase transplant activity, but their use is associated with a higher rate of both primary non-function and delayed graft function than cadaveric kidneys, due to a period of cold ischaemic damage superimposed on a period of warm ischaemia. We aimed to measure intra-renal resistance in machine perfused porcine kidneys subjected to different periods of warm ischaemic injury, with additional, varying, cold ischaemic times, in an attempt to mimic the injury suffered by NHBD kidneys and test the predictive power of viability testing. MATERIAL/METHODS: Landrace pigs were killed by lethal injection, and the kidneys were subjected to varying WITs of 10-90 minutes prior to explantation. Kidneys were subsequently stored for varying cold times of 2 to 48 hours. IRR (pressure/flow) was calculated during 6 hours cold pulsatile machine perfusion. RESULTS: For all WITs, IRR was higher at the start than at the end of machine perfusion (P<0.001). There was a strong correlation between IRR on MP, and WIT, but no correlation after 6 hours MP. Intra-renal resistance increased as kidneys were exposed to longer CITs; this effect was most marked for the longer WITs (P<0.004), However, the slope gradient was similar for the different WITs. CONCLUSIONS: Early IRR accurately reflects kidney in-situ WIT, and machine perfusion reduces IRR whilst cold ischaemia imposed on periods of warm ischaemia increases IRR and attenuates the beneficial effect of MP. Machine perfusion may partially ameliorate the effects of WIT in terms of IRR, and may prove useful in pre-transplant viability assessment of NHBD kidneys.