Somatostatin receptor 2 signaling promotes growth and tumor survival in small-cell lung cancer.

Somatostatin receptor 2 (SSTR2) is overexpressed in a majority of neuroendocrine neoplasms, including small-cell lung carcinomas (SCLCs). SSTR2 was previously considered an inhibitory receptor on cell growth, but its agonists had poor clinical responses in multiple clinical trials. The role of this receptor as a potential therapeutic target in lung cancer merits further investigation. We evaluated the expression of SSTR2 in a cohort of 96 primary tumors from patients with SCLC and found 48% expressed SSTR2. Correlation analysis in both CCLE and an SCLC RNAseq cohort confirmed high-level expression and identified an association between NEUROD1 and SSTR2. There was a significant association with SSTR2 expression profile and poor clinical outcome. We tested whether SSTR2 expression might contribute to tumor progression through activation of downstream signaling pathways, using in vitro and in vivo systems and downregulated SSTR2 expression in lung cancer cells by shRNA. SSTR2 downregulation led to increased apoptosis and dramatically decreased tumor growth in vitro and in vivo in multiple cell lines with decreased AMPKα phosphorylation and increased oxidative metabolism. These results demonstrate a role for SSTR2 signaling in SCLC and suggest that SSTR2 is a poor prognostic biomarker in SCLC and potential future therapeutic signaling target.

The RNA binding protein FXR1 is a new driver in the 3q26-29 amplicon and predicts poor prognosis in human cancers.

Aberrant expression of RNA-binding proteins has profound implications for cellular physiology and the pathogenesis of human diseases such as cancer. We previously identified the Fragile X-Related 1 gene (FXR1) as one amplified candidate driver gene at 3q26-29 in lung squamous cell carcinoma (SCC). FXR1 is an autosomal paralog of Fragile X mental retardation 1 and has not been directly linked to human cancers. Here we demonstrate that FXR1 is a key regulator of tumor progression and its overexpression is critical for nonsmall cell lung cancer (NSCLC) cell growth in vitro and in vivo. We identified the mechanisms by which FXR1 executes its regulatory function by forming a novel complex with two other oncogenes, protein kinase C, iota and epithelial cell transforming 2, located in the same amplicon via distinct binding mechanisms. FXR1 expression is a candidate biomarker predictive of poor survival in multiple solid tumors including NSCLCs. Because FXR1 is overexpressed and associated with poor clinical outcomes in multiple cancers, these results have implications for other solid malignancies.

Targeting SLC1a5-mediated glutamine dependence in non-small cell lung cancer.

We previously elucidated the pleotropic role of solute carrier family A1 member 5 (SLC1A5) as the primary transporter of glutamine (Gln), a modulator of cell growth and oxidative stress in non-small cell lung cancer (NSCLC). The aim of our study was to evaluate SLC1A5 as a potential new therapeutic target and candidate biomarker predictive of survival and response to therapy. SLC1A5 targeting was examined in a panel of NSCLC and human bronchial cell lines by RNA interference and by a small molecular inhibitor, gamma-l-glutamyl-p-nitroanilide (GPNA). The effects of targeting SLC1A5 on cell growth, Gln uptake, ATP level, autophagy and cell death were examined. Inactivation of SLC1A5 genetically or pharmacologically decreased Gln consumption, inhibited cell growth, induced autophagy and apoptosis in a subgroup of NSCLC cell lines that overexpress SLC1A5. Targeting SLC1A5 function decreased tumor growth in NSCLC xenografts. A multivariate Cox proportional hazards analysis indicates that patients with increased SLC1A5 mRNA expression have significantly shorter overall survival (p = 0.01, HR = 1.24, 95% CI: 1.05-1.46), adjusted for age, gender, smoking history and disease stage. In an immunohistochemistry study on 207 NSCLC patients, SLC1A5 protein expression remained highly significant prognostic value in both univariate (p < 0.0001, HR = 1.45, 95% CI: 1.15-1.50) and multivariate analyses (p = 0.04, HR = 1.22, 95% CI: 1.01-1.31). These results position SLC1A5 as a new candidate prognostic biomarker for selective targeting of Gln-dependent NSCLC.

In-depth proteomic analysis of nonsmall cell lung cancer to discover molecular targets and candidate biomarkers.

Advances in proteomic analysis of human samples are driving critical aspects of biomarker discovery and the identification of molecular pathways involved in disease etiology. Toward that end, in this report we are the first to use a standardized shotgun proteomic analysis method for in-depth tissue protein profiling of the two major subtypes of nonsmall cell lung cancer and normal lung tissues. We identified 3621 proteins from the analysis of pooled human samples of squamous cell carcinoma, adenocarcinoma, and control specimens. In addition to proteins previously shown to be implicated in lung cancer, we have identified new pathways and multiple new differentially expressed proteins of potential interest as therapeutic targets or diagnostic biomarkers, including some that were not identified by transcriptome profiling. Up-regulation of these proteins was confirmed by multiple reaction monitoring mass spectrometry. A subset of these proteins was found to be detectable and differentially present in the peripheral blood of cases and matched controls. Label-free shotgun proteomic analysis allows definition of lung tumor proteomes, identification of biomarker candidates, and potential targets for therapy.

Enhancement of systemic and sputum granulocyte response to inhaled endotoxin in people with the GSTM1 null genotype.

OBJECTIVE: To determine if the GSTM1 null genotype is a risk factor for increased inflammatory response to inhaled endotoxin. METHODS: 35 volunteers who had undergone inhalation challenge with a 20 000 endotoxin unit dose of Clinical Center Reference Endotoxin (CCRE) were genotyped for the GSTM1 null polymorphism. Parameters of airway and systemic inflammation observed before and after challenge were compared in GSTM1 null (n=17) and GSTM1 (n=18) sufficient volunteers. RESULTS: GSTM1 null volunteers had significantly increased circulating white blood cells (WBCs), polymorphonuclear neutrophils (PMNs), platelets and sputum PMNs (% sputum PMNs and PMNs/mg sputum) after CCRE challenge. GSTM1 sufficient volunteers had significant, but lower increases in circulating WBCs, PMNs and % sputum PMNs, and no increase in platelets or PMNs/mg sputum. Linear regression analysis adjusted for baseline values of the entire cohort revealed that the GSTM1 null genotype significantly increased circulating WBCs, platelets and % sputum PMNs after challenge. CONCLUSION: These data support the hypothesis that the GSTM1 null genotype is a risk factor for increased acute respiratory and systemic inflammatory response to inhaled CCRE. These data are consistent with other observations that the GSTM1 null genotype is associated with increased respiratory, systemic and cardiovascular effects linked to ambient air particulate matter exposure and indicate that the GSTM1 null genotype should be considered a risk factor for adverse health effects associated with exposure to environmental endotoxin.

The intractable cigarette 'filter problem'.

BACKGROUND: When lung cancer fears emerged in the 1950s, cigarette companies initiated a shift in cigarette design from unfiltered to filtered cigarettes. Both the ineffectiveness of cigarette filters and the tobacco industry's misleading marketing of the benefits of filtered cigarettes have been well documented. However, during the 1950s and 1960s, American cigarette companies spent millions of dollars to solve what the industry identified as the 'filter problem'. These extensive filter research and development efforts suggest a phase of genuine optimism among cigarette designers that cigarette filters could be engineered to mitigate the health hazards of smoking. OBJECTIVE: This paper explores the early history of cigarette filter research and development in order to elucidate why and when seemingly sincere filter engineering efforts devolved into manipulations in cigarette design to sustain cigarette marketing and mitigate consumers' concerns about the health consequences of smoking. METHODS: Relevant word and phrase searches were conducted in the Legacy Tobacco Documents Library online database, Google Patents, and media and medical databases including ProQuest, JSTOR, Medline and PubMed. RESULTS: 13 tobacco industry documents were identified that track prominent developments involved in what the industry referred to as the 'filter problem'. These reveal a period of intense focus on the 'filter problem' that persisted from the mid-1950s to the mid-1960s, featuring collaborations between cigarette producers and large American chemical and textile companies to develop effective filters. In addition, the documents reveal how cigarette filter researchers' growing scientific knowledge of smoke chemistry led to increasing recognition that filters were unlikely to offer significant health protection. One of the primary concerns of cigarette producers was to design cigarette filters that could be economically incorporated into the massive scale of cigarette production. The synthetic plastic cellulose acetate became the fundamental cigarette filter material. By the mid-1960s, the meaning of the phrase 'filter problem' changed, such that the effort to develop effective filters became a campaign to market cigarette designs that would sustain the myth of cigarette filter efficacy. CONCLUSIONS: This study indicates that cigarette designers at Philip Morris, British-American Tobacco, Lorillard and other companies believed for a time that they might be able to reduce some of the most dangerous substances in mainstream smoke through advanced engineering of filter tips. In their attempts to accomplish this, they developed the now ubiquitous cellulose acetate cigarette filter. By the mid-1960s cigarette designers realised that the intractability of the 'filter problem' derived from a simple fact: that which is harmful in mainstream smoke and that which provides the smoker with 'satisfaction' are essentially one and the same. Only in the wake of this realisation did the agenda of cigarette designers appear to transition away from mitigating the health hazards of smoking and towards the perpetuation of the notion that cigarette filters are effective in reducing these hazards. Filters became a marketing tool, designed to keep and recruit smokers as consumers of these hazardous products.

Atopic asthmatic subjects but not atopic subjects without asthma have enhanced inflammatory response to ozone.

BACKGROUND: Asthma is a known risk factor for acute ozone-associated respiratory disease. Ozone causes an immediate decrease in lung function and increased airway inflammation. The role of atopy and asthma in modulation of ozone-induced inflammation has not been determined. OBJECTIVE: We sought to determine whether atopic status modulates ozone response phenotypes in human subjects. METHODS: Fifty volunteers (25 healthy volunteers, 14 atopic nonasthmatic subjects, and 11 atopic asthmatic subjects not requiring maintenance therapy) underwent a 0.4-ppm ozone exposure protocol. Ozone response was determined based on changes in lung function and induced sputum composition, including airway inflammatory cell concentration, cell-surface markers, and cytokine and hyaluronic acid concentrations. RESULTS: All cohorts experienced similar decreases in lung function after ozone. Atopic and atopic asthmatic subjects had increased sputum neutrophil numbers and IL-8 levels after ozone exposure; values did not significantly change in healthy volunteers. After ozone exposure, atopic asthmatic subjects had significantly increased sputum IL-6 and IL-1beta levels and airway macrophage Toll-like receptor 4, Fc(epsilon)RI, and CD23 expression; values in healthy volunteers and atopic nonasthmatic subjects showed no significant change. Atopic asthmatic subjects had significantly decreased IL-10 levels at baseline compared with healthy volunteers; IL-10 levels did not significantly change in any group with ozone. All groups had similar levels of hyaluronic acid at baseline, with increased levels after ozone exposure in atopic and atopic asthmatic subjects. CONCLUSION: Atopic asthmatic subjects have increased airway inflammatory responses to ozone. Increased Toll-like receptor 4 expression suggests a potential pathway through which ozone generates the inflammatory response in allergic asthmatic subjects but not in atopic subjects without asthma.

Comparative airway inflammatory response of normal volunteers to ozone and lipopolysaccharide challenge.

Ozone and lipopolysaccharide (LPS) are environmental pollutants with adverse health effects noted in both healthy and asthmatic individuals. The authors and others have shown that inhalation of ozone and LPS both induce airway neutrophilia. Based on these similarities, the authors tested the hypothesis that common biological factors determine response to these two different agents. Fifteen healthy, nonasthmatic volunteers underwent a 0.4 part per million ozone exposure for 2 h while performing intermittent moderate exercise. These same subjects underwent an inhaled LPS challenge with 20,000 LPS units of Clinical Center Reference LPS, with a minimum of 1 month separating these two challenge sessions. Induced sputum was obtained 24 h before and 4-6 h after each exposure session. Sputum was assessed for total and differential cell counts and expression of cell surface proteins as measured by flow cytometry. Sputum supernatants were assayed for cytokine concentration. Both ozone and LPS challenge augmented sputum neutrophils and subjects' responses were significantly correlated (R = .73) with each other. Ozone had greater overall influence on cell surface proteins by modifying both monocytes (CD14, human leukocyte antigen [HLA]-DR, CD11b) and macrophages (CD11b, HLA-DR) versus LPS where CD14 and HLA-DR were modified only on monocytes. However, LPS significantly increased interleukin (IL)-1beta, IL-6, and tumor necrosis factor (TNF)-alpha, with no significant increases seen after ozone challenge. Ozone and LPS exposure in healthy volunteers induce similar neutrophil responses in the airways; however, downstream activation of innate immune responses differ, suggesting that oxidant versus bacterial air pollutants may be mediated by different mechanisms.

Low-level ozone exposure induces airways inflammation and modifies cell surface phenotypes in healthy humans.

The effects of low-level ozone exposure (0.08 ppm) on pulmonary function in healthy young adults are well known; however, much less is known about the inflammatory and immunomodulatory effects of low-level ozone in the airways. Techniques such as induced sputum and flow cytometry make it possible to examine airways inflammatory responses and changes in immune cell surface phenotypes following low-level ozone exposure. The purpose of this study was to determine if exposure to 0.08 parts per million ozone for 6.6 h induces inflammation and modifies immune cell surface phenotypes in the airways of healthy adult subjects. Fifteen normal volunteers underwent an established 0.08 part per million ozone exposure protocol to characterize the effect of ozone on airways inflammation and immune cell surface phenotypes. Induced sputum and flow cytometry were used to assess these endpoints 24 h before and 18 h after exposure. The results showed that exposure to 0.08 ppm ozone for 6.6 h induced increased airway neutrophils, monocytes, and dendritic cells and modified the expression of CD14, HLA-DR, CD80, and CD86 on monocytes 18 h following exposure. Exposure to 0.08 parts per million ozone is associated with increased airways inflammation and promotion of antigen-presenting cell phenotypes 18 hours following exposure. These findings need to be replicated in a similar experiment that includes a control air exposure.

The glutathione-S-transferase Mu 1 null genotype modulates ozone-induced airway inflammation in human subjects.

BACKGROUND: The glutathione-S-transferase Mu 1 (GSTM1) null genotype has been reported to be a risk factor for acute respiratory disease associated with increases in ambient air ozone levels. Ozone is known to cause an immediate decrease in lung function and increased airway inflammation. However, it is not known whether GSTM1 modulates these ozone responses in vivo in human subjects. OBJECTIVE: The purpose of this study was to determine whether the GSTM1 null genotype modulates ozone responses in human subjects. METHODS: Thirty-five healthy volunteers were genotyped for the GSTM1 null mutation and underwent a standard ozone exposure protocol to determine whether lung function and inflammatory responses to ozone were different between the 19 GSTM1 wild type and 16 GSTM1 null volunteers. RESULTS: GSTM1 did not modulate lung function responses to acute ozone. Granulocyte influx 4 hours after challenge was similar between GSTM1 normal and null volunteers. However, GSTM1 null volunteers had significantly increased airway neutrophils 24 hours after challenge, as well as increased expression of HLA-DR on airway macrophages and dendritic cells. CONCLUSION: The GSTM1 null genotype is associated with increased airways inflammation 24 hours after ozone exposure, which is consistent with the lag time observed between increased ambient air ozone exposure and exacerbations of lung disease.

Family alert: implementing direct family activation of a pediatric rapid response team.

A hospital's "no false alams" policy has been validated by staff's and families' appropriate activation of the rapid response team.

xCT (SLC7A11)-mediated metabolic reprogramming promotes non-small cell lung cancer progression.

Many tumors increase uptake and dependence on glucose, cystine or glutamine. These basic observations on cancer cell metabolism have opened multiple new diagnostic and therapeutic avenues in cancer research. Recent studies demonstrated that smoking could induce the expression of xCT (SLC7A11) in oral cancer cells, suggesting that overexpression of xCT may support lung tumor progression. We hypothesized that overexpression of xCT occurs in lung cancer cells to satisfy the metabolic requirements for growth and survival. Our results demonstrated that 1) xCT was highly expressed at the cytoplasmic membrane in non-small cell lung cancer (NSCLC), 2) the expression of xCT was correlated with advanced stage and predicted a worse 5-year survival, 3) targeting xCT transport activity in xCT overexpressing NSCLC cells with sulfasalazine decreased cell proliferation and invasion in vitro and in vivo and 4) increased dependence on glutamine was observed in xCT overexpressed normal airway epithelial cells. These results suggested that xCT regulate metabolic requirements during lung cancer progression and be a potential therapeutic target in NSCLC.

Probiotic administration and the incidence of nosocomial infection in pediatric intensive care: a randomized placebo-controlled trial.

OBJECTIVE: To evaluate the efficacy of probiotics in reducing the rates of nosocomial infection in pediatric intensive care. DESIGN: Randomized, double-blind, placebo-controlled trial. SETTING: A 16-bed pediatric intensive care unit in a university-affiliated children's hospital. PATIENTS: Sixty-one pediatric patients were enrolled from April 2004 until December 2004. Screening of all patients admitted occurred on a daily basis. Patients were excluded if they had the following: evidence/suspicion of intestinal perforation, evidence/suspicion of mechanical gastrointestinal obstruction, absolute neutrophil count

Using Embedded Sensors in Independent Living to Predict Gait Changes and Falls.

This study explored using Big Data, totaling 66 terabytes over 10 years, captured from sensor systems installed in independent living apartments to predict falls from pre-fall changes in residents' Kinect-recorded gait parameters. Over a period of 3 to 48 months, we analyzed gait parameters continuously collected for residents who actually fell ( n = 13) and those who did not fall ( n = 10). We analyzed associations between participants' fall events ( n = 69) and pre-fall changes in in-home gait speed and stride length ( n = 2,070). Preliminary results indicate that a cumulative change in speed over time is associated with the probability of a fall ( p < .0001). The odds of a resident falling within 3 weeks after a cumulative change of 2.54 cm/s is 4.22 times the odds of a resident falling within 3 weeks after no change in in-home gait speed. Results demonstrate using sensors to measure in-home gait parameters associated with the occurrence of future falls.

Randomized Trial of Intelligent Sensor System for Early Illness Alerts in Senior Housing.

OBJECTIVES: Measure the clinical effectiveness and cost effectiveness of using sensor data from an environmentally embedded sensor system for early illness recognition. This sensor system has demonstrated in pilot studies to detect changes in function and in chronic diseases or acute illnesses on average 10 days to 2 weeks before usual assessment methods or self-reports of illness. DESIGN: Prospective intervention study in 13 assisted living (AL) communities of 171 residents randomly assigned to intervention (n=86) or comparison group (n=85) receiving usual care. METHODS: Intervention participants lived with the sensor system an average of one year. MEASUREMENTS: Continuous data collected 24 hours/7 days a week from motion sensors to measure overall activity, an under mattress bed sensor to capture respiration, pulse, and restlessness as people sleep, and a gait sensor that continuously measures gait speed, stride length and time, and automatically assess for increasing fall risk as the person walks around the apartment. Continuously running computer algorithms are applied to the sensor data and send health alerts to staff when there are changes in sensor data patterns. RESULTS: The randomized comparison group functionally declined more rapidly than the intervention group. Walking speed and several measures from GaitRite, velocity, step length left and right, stride length left and right, and the fall risk measure of functional ambulation profile (FAP) all had clinically significant changes. The walking speed increase (worse) and velocity decline (worse) of 0.073 m/s for comparison group exceeded 0.05 m/s, a value considered to be a minimum clinically important difference. No differences were measured in health care costs. CONCLUSIONS: These findings demonstrate that sensor data with health alerts and fall alerts sent to AL nursing staff can be an effective strategy to detect and intervene in early signs of illness or functional decline.

Testing non-wearable fall detection methods in the homes of older adults.

In this paper, we describe two longitudinal studies in which fall detection sensor technology was tested in the homes of older adults. The first study tested Doppler radar, a two-webcam system, and a depth camera system in ten apartments for two years. This continuous data collection allowed us to investigate the real-world setting of target users and compare the advantages and limitations of each sensor modality. Based on this study, the depth camera was chosen for a current ongoing study in which depth camera systems have been installed in 94 additional older adult apartments. We include a discussion of the different sensor systems, the pros and cons of each, and results of the fall detection and false alarms in the older adult homes.

Preclinical Evaluation of 4-[18F]Fluoroglutamine PET to Assess ASCT2 Expression in Lung Cancer.

PURPOSE: Alanine-serine-cysteine transporter 2 (ASCT2) expression has been demonstrated as a promising lung cancer biomarker. (2S,4R)-4-[(18)F]Fluoroglutamine (4-[(18)F]fluoro-Gln) positron emission tomography (PET) was evaluated in preclinical models of non-small cell lung cancer as a quantitative, non-invasive measure of ASCT2 expression. PROCEDURES: In vivo microPET studies of 4-[(18)F]fluoro-Gln uptake were undertaken in human cell line xenograft tumor-bearing mice of varying ASCT2 levels, followed by a genetically engineered mouse model of epidermal growth factor receptor (EGFR)-mutant lung cancer. The relationship between a tracer accumulation and ASCT2 levels in tumors was evaluated by IHC and immunoblotting. RESULT: 4-[(18)F]Fluoro-Gln uptake, but not 2-deoxy-2-[(18)F]fluoro-D-glucose, correlated with relative ASCT2 levels in xenograft tumors. In genetically engineered mice, 4-[(18)F]fluoro-Gln accumulation was significantly elevated in lung tumors, relative to normal lung and cardiac tissues. CONCLUSIONS: 4-[(18)F]Fluoro-Gln PET appears to provide a non-invasive measure of ASCT2 expression. Given the potential of ASCT2 as a lung cancer biomarker, this and other tracers reflecting ASCT2 levels could emerge as precision imaging diagnostics in this setting.

The airway epithelium undergoes metabolic reprogramming in individuals at high risk for lung cancer.

The molecular determinants of lung cancer risk remain largely unknown. Airway epithelial cells are prone to assault by risk factors and are considered to be the primary cell type involved in the field of cancerization. To investigate risk-associated changes in the bronchial epithelium proteome that may offer new insights into the molecular pathogenesis of lung cancer, proteins were identified in the airway epithelial cells of bronchial brushing specimens from risk-stratified individuals by shotgun proteomics. Differential expression of selected proteins was validated by parallel reaction monitoring mass spectrometry in an independent set of individual bronchial brushings. We identified 2,869 proteins, of which 312 proteins demonstrated a trend in expression. Pathway analysis revealed enrichment of carbohydrate metabolic enzymes in high-risk individuals. Glucose consumption and lactate production were increased in human bronchial epithelial BEAS2B cells treated with cigarette smoke condensate for 7 months. Increased lipid biosynthetic capacity and net reductive carboxylation were revealed by metabolic flux analyses of [U-13C5] glutamine in this in vitro model, suggesting profound metabolic reprogramming in the airway epithelium of high-risk individuals. These results provide a rationale for the development of potentially new chemopreventive strategies and selection of patients for surveillance programs.

Inhibition of the Biosynthesis of Prostaglandin E2 By Low-Dose Aspirin: Implications for Adenocarcinoma Metastasis.

Meta-analyses have demonstrated that low-dose aspirin reduces the risk of developing adenocarcinoma metastasis, and when colon cancer is detected during aspirin treatment, there is a remarkable 83% reduction in risk of metastasis. As platelets participate in the metastatic process, the antiplatelet action of low-dose aspirin likely contributes to its antimetastatic effect. Cycloxooxygenase-2 (COX-2)-derived prostaglandin E2 (PGE2) also contributes to metastasis, and we addressed the hypothesis that low-dose aspirin also inhibits PGE2 biosynthesis. We show that low-dose aspirin inhibits systemic PGE2 biosynthesis by 45% in healthy volunteers (P < 0.0001). Aspirin is found to be more potent in colon adenocarcinoma cells than in the platelet, and in lung adenocarcinoma cells, its inhibition is equivalent to that in the platelet. Inhibition of COX by aspirin in colon cancer cells is in the context of the metastasis of colon cancer primarily to the liver, the organ exposed to the same high concentrations of aspirin as the platelet. We find that the interaction of activated platelets with lung adenocarcinoma cells upregulates COX-2 expression and PGE2 biosynthesis, and inhibition of platelet COX-1 by aspirin inhibits PGE2 production by the platelet-tumor cell aggregates. In conclusion, low-dose aspirin has a significant effect on extraplatelet cyclooxygenase and potently inhibits COX-2 in lung and colon adenocarcinoma cells. This supports a hypothesis that the remarkable prevention of metastasis from adenocarcinomas, and particularly from colon adenocarcinomas, by low-dose aspirin results from its effect on platelet COX-1 combined with inhibition of PGE2 biosynthesis in metastasizing tumor cells. Cancer Prev Res; 9(11); 855-65. ©2016 AACR.

A new challenge in pediatric obesity: pediatric hyperglycemic hyperosmolar syndrome.

OBJECTIVES: To describe four adolescents with hyperglycemic hyperosmolar syndrome, an uncommon presentation of type 2 diabetes in pediatric patients. DESIGN: Case report. SETTING: Two tertiary pediatric intensive care units in university teaching hospitals. PATIENTS: Four obese adolescents with hyperglycemic hyperosmolar syndrome associated with type 2 diabetes mellitus. INTERVENTIONS: Isotonic fluid resuscitation and insulin. MEASUREMENTS AND MAIN RESULTS: Two of the four patients died. The first patient died within the first 24 hrs of hyperglycemic hyperosmolar syndrome presumably due to hypovolemic shock. The second patient, who died, developed rhabdomyolysis and multiple-system organ failure after a prolonged intensive care unit stay. The third and fourth patients were discharged from the hospital in good health. None of the patients had cerebral edema on head computed tomography, despite differences in fluid and insulin management. CONCLUSIONS: Pediatric patients with hyperglycemic hyperosmolar syndrome have a high mortality rate and may experience multiple complications such as rhabdomyolysis and hypovolemic shock. Treatment strategies to reduce mortality are unclear and warrant further investigation.