Methods to study xenografted human cancer in genetically diverse mice.

Xenografting human cancer tissues into mice to test new cures against cancers is critical for understanding and treating the disease. However, only a few inbred strains of mice are used to study cancers, and derivatives of mainly one strain, mostly NOD/ShiLtJ, are used for therapy efficacy studies. As it has been demonstrated when human cancer cell lines or patient-derived tissues (PDX) are xenografted into mice, the neoplastic cells are human but the supporting cells that comprise the tumor (the stroma) are from the mouse. Therefore, results of studies of xenografted tissues are influenced by the host strain. We previously published that when the same neoplastic cells are xenografted into different mouse strains, the pattern of tumor growth, histology of the tumor, number of immune cells infiltrating the tumor, and types of circulating cytokines differ depending on the strain. Therefore, to better comprehend the behavior of cancer in vivo, one must xenograft multiple mouse strains. Here we describe and report a series of methods that we used to reveal the genes and proteins expressed when the same cancer cell line, MDA-MB-231, is xenografted in different hosts. First, using proteomic analysis, we show how to use the same cell line in vivo to reveal the protein changes in the neoplastic cell that help it adapt to its host. Then, we show how different hosts respond molecularly to the same cell line. We also find that using multiple strains can reveal a more suitable host than those traditionally used for a "difficult to xenograft" PDX. In addition, using complex trait genetics, we illustrate a feasible method for uncovering the alleles of the host that support tumor growth. Finally, we demonstrate that Diversity Outbred mice, the epitome of a model of mouse-strain genetic diversity, can be xenografted with human cell lines or PDX using 2-deoxy-D-glucose treatment.

Genetically diverse mouse platform to xenograft cancer cells.

The lack of genetically diverse preclinical animal models in basic biology and efficacy testing has been cited as a potential cause of failure in clinical trials. We developed and characterized five diverse RAG1 null mouse strains as models that allow xenografts to grow. In these strains, we characterized the growth of breast cancer, leukemia and glioma cell lines. We found a wide range of growth characteristics that were far more dependent on strain than tumor type. For the breast cancer cell line, we characterized the spectrum of xenograft/tumor growth at structural, histological, cellular and molecular levels across each strain, and found that each strain captures unique structural components of the stroma. Furthermore, we showed that the increase in tumor-infiltrating myeloid CD45+ cells and the amount of circulating cytokine IL-6 and chemokine KC (also known as CXCL1) is associated with a higher tumor size in different strains. This resource is available to study established human xenografts, as well as difficult-to-xenograft tumors and growth of hematopoietic stems cells, and to decipher the role of myeloid cells in the development of spontaneous cancers.

Anesthesia Patient Safety: Next Steps to Improve Worldwide Perioperative Safety by 2030.

Patient safety is a core principle of anesthesia care worldwide. The specialty of anesthesiology has been a leader in medicine for the past half century in pursuing patient safety research and implementing standards of care and systematic improvements in processes of care. Together, these efforts have dramatically reduced patient harm associated with anesthesia. However, improved anesthesia patient safety has not been uniformly obtained worldwide. There are unique differences in patient safety outcomes between countries and regions in the world. These differences are often related to factors such as availability, support, and use of health care resources, trained personnel, patient safety outcome data collection efforts, standards of care, and cultures of safety and teamwork in health care facilities. This article provides insights from national anesthesia society leaders from 13 countries around the world. The countries they represent are diverse geographically and in health care resources. The authors share their countries' current and future initiatives in anesthesia patient safety. Ten major patient safety issues are common to these countries, with several of these focused on the importance of extending initiatives into the full perioperative as well as intraoperative environments. These issues may be used by anesthesia leaders around the globe to direct collaborative efforts to improve the safety of patients undergoing surgery and anesthesia in the coming decade.

The Evolution of the Anesthesia Patient Safety Movement in America: Lessons Learned and Considerations to Promote Further Improvement in Patient Safety.

Ellison C. Pierce, Jr., M.D., and a small number of specialty leaders and scientists formed a remarkable, diverse team in the mid-1980s to address a dual crisis: a safety crisis for anesthetized patients and a medical malpractice insurance crisis for anesthesiologists. This cohesive team's efforts led to the formation of the Anesthesia Patient Safety Foundation, the American Society of Anesthesiologists's Committees on Standards of Care and on Patient Safety and Risk Management, and the society's Closed Claims Project. The commonality of leaders and members of the Anesthesia Patient Safety Foundation and American Society of Anesthesiologists initiatives provided the strong coordination needed for their efforts to effect change, introduce standards of care and practice parameters, obtain financial support needed to grow patient safety-oriented new knowledge, integrate industry and other relevant leaders outside of anesthesiology, and involve all anesthesia professions. By implementing successful patient safety initiatives, they promoted the recognition that anesthesiology and patient safety are inextricably linked.

Pulmonary Aspiration of Gastric Contents: A Closed Claims Analysis.

BACKGROUND: Perioperative pulmonary aspiration of gastric contents has been associated with severe morbidity and death. The primary aim of this study was to identify outcomes and patient and process of care risk factors associated with gastric aspiration claims in the Anesthesia Closed Claims Project. The secondary aim was to assess these claims for appropriateness of care. The hypothesis was that these data could suggest opportunities to reduce either the risk or severity of perioperative pulmonary aspiration. METHODS: Inclusion criteria were anesthesia malpractice claims in the American Society of Anesthesiologists Closed Claims Project that were associated with surgical, procedural, or obstetric anesthesia care with the year of the aspiration event 2000 to 2014. Claims involving pulmonary aspiration were identified and assessed for patient and process factors that may have contributed to the aspiration event and outcome. The standard of care was assessed for each claim. RESULTS: Aspiration of gastric contents accounted for 115 of the 2,496 (5%) claims in the American Society of Anesthesiologists Closed Claims Project that met inclusion criteria. Death directly related to pulmonary aspiration occurred in 66 of the 115 (57%) aspiration claims. Another 16 of the 115 (14%) claims documented permanent severe injury. Seventy of the 115 (61%) patients who aspirated had either gastrointestinal obstruction or another acute intraabdominal process. Anesthetic management was judged to be substandard in 62 of the 115 (59%) claims. CONCLUSIONS: Death and permanent severe injury were common outcomes of perioperative pulmonary aspiration of gastric contents in this series of closed anesthesia malpractice claims. The majority of the patients who aspirated had either gastrointestinal obstruction or acute intraabdominal processes. Anesthesia care was frequently judged to be substandard. These findings suggest that clinical practice modifications to preoperative assessment and anesthetic management of patients at risk for pulmonary aspiration may lead to improvement of their perioperative outcomes.

Perioperative Ulnar Neuropathy: A Contemporary Estimate of Incidence and Risk Factors.

BACKGROUND: Retrospective and prospective studies 2 decades ago from the authors' institution reported the incidence of perioperative ulnar neuropathy persisting for at least several months in a noncardiac adult surgical population to be between 30 and 40 per 100,000 cases. The aim of this project was to assess the incidence and explore risk factors for perioperative ulnar neuropathy in a recent cohort of patients from the same institution using a similar definition for ulnar neuropathy. METHODS: We performed a retrospective incidence and case-control study of all adults (≥18 years) undergoing noncardiac procedures with anesthesia services between 2011 and 2015. Each incident case of persistent ulnar neuropathy within 6 months of surgery was matched by age, sex, procedure date, and procedure type to 5 surgical patient controls. For the case-control study, separate conditional logistic regression analyses were performed to assess specific risk factors including the patient's body position and arm position, as well as body mass index (BMI), surgical duration, and selected patient comorbidities. RESULTS: Persistent ulnar neuropathy of at least 2 months duration was found in 22 of 324,124 anesthetics for patients who underwent these procedures during the study period for an incidence rate of 6.8 (95% confidence interval [CI], 4.3-10.3) per 100,000 anesthetics. The incidence of ulnar neuropathy was higher in men compared to women (10.7 vs 3.0 per 100,000; P = .016). From the matched case-control study, the odds of ulnar neuropathy increased with higher BMI (odds ratio [OR] = 1.67 [1.16-2.42] per 5 kg/m2 increase in BMI; P = .006), history of cancer (OR = 6.46 [1.64-25.49]; P = .008), longer procedures (OR = 1.53 [1.18-1.99] per hour; P = .001), and when 1 or both arms were tucked during surgery (OR = 6.16 [1.85-20.59]; P = .003). CONCLUSIONS: The incidence of persistent perioperative ulnar neuropathy observed in this study was lower than the incidence reported 2 decades ago from the same institution and using a similar definition for ulnar neuropathy. Several of the previously reported risk factors continue to be associated with the development of persistent perioperative ulnar neuropathy, providing ongoing targets for practice changes that might further decrease the incidence of this problem.

Black Seed Oil and Perioperative Serotonin Syndrome: A Case Report.

Perioperative serotonin syndrome has been associated with a number of medications and herbal supplements. We report a patient who developed serotonin syndrome immediately after an endoscopic procedure in which the preoperative use of black seed oil appears to have played a role in stimulating the syndrome. Black seed oil has not been previously reported in association with perioperative serotonin syndrome. Anesthesia professionals should be aware that patients taking black seed oil supplements may develop serotonin syndrome postoperatively.

Safety of Sedation for Patients Undergoing Bone Marrow Biopsy and Aspiration While Febrile.

OBJECTIVE: To determine the risks and outcomes of providing sedation to febrile patients scheduled for bone marrow aspiration or biopsy procedures. PATIENTS AND METHODS: During the 4-year period from January 1, 2013, through December 31, 2016, data from the periprocedural courses of 12,134 consecutive patients in an outpatient procedure center at a large tertiary medical center were collected retrospectively and analyzed to determine whether febrile patients undergoing bone marrow aspiration and/or biopsy with propofol sedation present a unique patient safety risk. RESULTS: Eighty-four patients (0.7%) had preprocedural temperatures of greater than or equal to 38.3°C. Of these, 6 required unanticipated hospital admission for sustained hypoxemia and symptoms suggesting pneumonia. All 6 of these patients had a productive cough and room air oxygen saturations of less than 92% before their procedures. These 6 patients were diagnosed during their hospitalizations with either confirmed or presumed community-acquired pneumonia. All recovered without pulmonary sequelae. Only 2 of the other 78 febrile patients required unanticipated hospital admission, for both general weakness and dehydration. CONCLUSION: Our findings suggest that patients who are febrile and who also have productive coughs and oxyhemoglobin saturations by pulse oximetry of less than 92% would be best served with outpatient evaluation of their pulmonary symptoms before undergoing their elective bone marrow aspiration procedures. In contrast, febrile patients without pulmonary symptoms fare well.

Serotonergic medications, herbal supplements, and perioperative serotonin syndrome.

PURPOSE: Perioperative use of serotonergic agents increases the risk of serotonin syndrome. We describe the occurrence of serotonin syndrome after fentanyl use in two patients taking multiple serotonergic agents. CLINICAL FEATURES: Two patients who had been taking multiple serotonergic medications or herbal supplements (one patient taking fluoxetine, turmeric supplement, and acyclovir; the other taking fluoxetine and trazodone) developed serotonin syndrome perioperatively when undergoing outpatient procedures. Both experienced acute loss of consciousness and generalized myoclonus after receiving fentanyl. In one patient, the serotonin syndrome promptly resolved after naloxone administration. In the other patient, the onset of serotonin syndrome was delayed and manifested after discharge, most likely attributed to the intraoperative use of midazolam for sedation. CONCLUSION: Even small doses of fentanyl administered to patients taking multiple serotonergic medications and herbal supplements may trigger serotonin syndrome. Prompt reversal of serotonin toxicity in one patient by naloxone illustrates the likely opioid-mediated pathogenesis of serotonin syndrome in this case. It also highlights that taking serotonergic agents concomitantly can produce the compounding effect that causes serotonin syndrome. The delayed presentation of serotonin syndrome in the patient who received a large dose of midazolam suggests that outpatients taking multiple serotonergic drugs who receive benzodiazepines may require longer postprocedural monitoring.

Falls From the O.R. or Procedure Table.

Patient safety secured by constant vigilance remains a primary responsibility of every anesthesia professional. Although significant attention has been focused on patient falls occurring before and after surgery, a potentially catastrophic complication is when patients fall off an operating room or procedure table during anesthesia care. Because such events are (fortunately) uncommon, and because very little information is published in our literature, we queried 2 independent closed claims databases (the American Society of Anesthesiologists Closed Claims Project and the secure records of a private, anesthesia specialty-specific liability insurer) for information. We acquired documentation of patient events where a fall occurred during anesthesia care, noting the surrounding conditions of the provider, the patient, and the environment at the time of the event. We identified 21 claims (1.2% of cases) from the American Society of Anesthesiologists Closed Claims Project, while information from a private liability insurer identified falls in only 0.07% of cases. The percentage of these patients under general, regional, or monitored anesthesia care anesthesia was 71.5%, 19.5%, and 9.5%, respectively. To educate personnel about these uncommon events, we summarized this cohort with illustrative examples in a series of mini-case reports, noting that both inpatients and outpatients undergoing a broad array of procedures with various anesthetic techniques within and outside operating rooms may be vulnerable to patient falls. Based on detailed reports, we created 2 supplementary videos to further illuminate some of the unique mechanisms by which these events and their resulting injuries occur. When such information was available, we also noted the associated liability costs of defending and settling malpractice claims associated with these events. Our goal is to inform anesthesia and perioperative personnel about the common patient, provider, and environmental risk factors that appear to contribute to these mishaps, and suggest key strategies to mitigate the risks.

Anesthetic Considerations for Angelman Syndrome: Case Series and Review of the Literature.

BACKGROUND: Angelman syndrome is a rare neurodevelopmental disorder characterized by intellectual disability, severe speech impairment, ataxia, seizures, happy demeanor, distinctive craniofacial features, high vagal tone, and gamma-amino butyric acid receptor abnormalities. The aim of this report is to review our experience of patients with Angelman syndrome undergoing anesthetic management. METHODS: We retrospectively reviewed perioperative course of patients with Angelman syndrome who underwent procedures under anesthesia from 2000 to 2016. RESULTS: Six patients with Angelman syndrome underwent 18 procedures; 14 performed under general anesthesia, and 4 with monitored anesthetic care, many for minor procedures (e.g., dental and diagnostic). Five patients had profound developmental delay and were nonverbal and 4 of them had epilepsy. The perioperative courses were uncomplicated except a 2 year-old girl having an intraoperative bronchospasm, a 16 year-old girl requiring flumazenil administration, and 28 year-old man who was electively intubated with a videolaryngoscope because of airway management concerns. No patients were documented as having postoperative pain. CONCLUSIONS: Angelman syndrome patients often require anesthesia for relatively innocuous procedures, and their speech impairment and happy demeanor can confound postoperative pain assessment. Patients can have atypical responses to benzodiazepines. Craniofacial abnormalities can complicate airway management. Although not encountered in this series, anesthesiologists need to be aware that Angelman syndrome patients have developed malignant bradydysrhythmias while anesthetized.

Neuropathies after surgery: Anatomical considerations of pathologic mechanisms.

Positioning-related injuries caused during surgery under anesthesia are most likely multifactorial. Pathologic mechanical forces alone (overstretching and/or ischemia from direct compression) may not fully explain postsurgical neuropathy with recent evidence implicating patient-specific factors or perioperative inflammatory responses spatially and even temporally divorced from the anatomical region of injury. The aim of this introductory article is to provide an overview of anatomic considerations of these mechanical forces on soft and nervous tissues along with factors that may compound compression or stretch injury. Three subsequent articles will address specific positioning-related anatomic considerations of the (1) upper extremities, (2) lower extremities, and (3) central nervous system and soft tissues.