Jun Tashiro

Therapeutic benefits of young, but not old, adipose-derived mesenchymal stem cells in a chronic mouse model of bleomycin-induced pulmonary fibrosis.

The observation that pulmonary inflammatory lesions and bleomycin (BLM)-induced pulmonary fibrosis spontaneously resolve in young mice, whereas remaining irreversible in aged mice suggests that impairment of pulmonary regeneration and repair is associated with aging. Because mesenchymal stem cells (MSCs) may promote repair after injury, we postulated that differences in MSCs from aged mice may underlie postinjury fibrosis in aging. The potential for young-donor MSCs to inhibit BLM-induced pulmonary fibrosis in aged male mice (>22 months) has not been studied. Adipose-derived MSCs (ASCs) from young (4 months) and old (22 months) male mice were infused 1 day after intratracheal BLM administration. At 21-day sacrifice, aged BLM mice demonstrated lung fibrosis by Ashcroft score, collagen content, and α(v)-integrin messenger RNA (mRNA) expression. Lung tissue from aged BLM mice receiving young ASCs exhibited decreased fibrosis, matrix metalloproteinase (MMP)-2 activity, oxidative stress, and markers of apoptosis vs BLM controls. Lung mRNA expression of tumor necrosis factor-alpha was also decreased in aged BLM mice receiving young-donor ASCs vs BLM controls. In contrast, old-donor ASC treatment in aged BLM mice did not reduce fibrosis and related markers. On examination of the cells, young-donor ASCs had decreased mRNA expression of MMP-2, insulin-like growth factor (IGF) receptor, and protein kinase B (AKT) activation compared with old-donor ASCs. These results show that the BLM-induced pulmonary fibrosis in aged mice could be blocked by young-donor ASCs and that the mechanisms involve changes in collagen turnover and markers of inflammation.

Malignant tumors of the parotid gland in children: incidence and outcomes.

Background Population-based analysis of the incidence, demographics, and management outcomes in children with malignant tumors of the parotid gland. Methods Surveillance, Epidemiology, and End Results database (1973–2009) was researched for all patients younger than 20 years. Results Overall, 284 patients were identified. Annual incidence of these tumors was 1.43 cases per million. The highest incidence occurred in girls (0.86/1,000,000), black children (0.849/1,000,000), and adolescents (1.56/1,000,000). Median age at diagnosis was 13.5 years. Most patients were 10 years or older (n = 256, 90%). Most patients presented with local disease (n = 207, 76%). Only 3% had metastasis at time of diagnosis. Most tumors were mucoepidermoid carcinomas (n = 139, 49%) or acinar cell carcinomas (n = 113, 40%). There were no differences in survival between mucoepidermoid and acinar cell carcinomas (96% vs 98% respectively, P = 0.317). Overall mortality was 4.6% over the study period. Overall survival was 96% at 5 years, 95% at 10 years, and 83% at 20 years. Adolescents had significantly higher mortality rates (7.1% vs 1.6% for children <15 years of age, P = 0.23). Multivariate analysis identified the use of adjuvant radiation therapy (hazard ratio, 6.01; 95% confidence interval, 1.15–31.45; P = 0.034) as the only independent predictor of poor outcome. Conclusions Malignant parotid gland tumors are most common in adolescents, and this subgroup has worse outcomes. The role of radiotherapy remains controversial.

Clinical outcomes for Conduits and Scaffolds in peripheral nerve repair.

The gold standard of peripheral nerve repair is nerve autograft when tensionless repair is not possible. Use of nerve autograft has several shortcomings, however. These include limited availability of donor tissue, sacrifice of a functional nerve, and possible neuroma formation. In order to address these deficiencies, researchers have developed a variety of biomaterials available for repair of peripheral nerve gaps. We review the clinical studies published in the English literature detailing outcomes and reconstructive options. Regardless of the material used or the type of nerve repaired, outcomes are generally similar to nerve autograft in gaps less than 3 cm. New biomaterials currently under preclinical evaluation may provide improvements in outcomes.

Reduced Hospital Mortality With Surgical Ligation of Patent Ductus Arteriosus in Premature, Extremely Low Birth Weight Infants: A Propensity Score-matched Outcome Study.

Objectives:To evaluate outcomes after surgical ligation (SL) of patent ductus arteriosus (PDA) in premature, extremely low birth weight (ELBW) infants. Background:Optimal management of PDA in this specialized population remains undefined. Currently, surgical therapy is largely reserved for infants failing medical management. To date, a large-scale, risk-matched population-based study has not been performed to evaluate differences in mortality and resource utilization. Methods:Data on identified premature (<37 weeks) and ELBW (<1000 g) infants with PDA (International Classification of Diseases, 9th revision, Clinical Modification, 747.0) and respiratory distress (769) were obtained from Kids’ Inpatient Database (2003–2009). Results:Overall, 12,470 cases were identified, with 3008 undergoing SL. Propensity score-matched analysis of 1620 SL versus 1584 non-SL found reduced mortality (15% vs 26%) and more routine disposition (48% vs 41%) for SL (P < 0.001). SL had longer length of stay and higher total cost (P < 0.001). On multivariate analysis, SL mortality predictors were necrotizing enterocolitis (NEC; surgical odds ratio, 5.95; medical odds ratio, 4.42) and sepsis (3.43) (P < 0.006). Length of stay increased with bronchopulmonary dysplasia (BPD; 1.77), whereas total cost increased with surgical NEC (1.82) and sepsis (1.26) (P < 0.04). Non-SL mortality predictors were NEC (surgical, 76.3; medical, 6.17), sepsis (2.66), and intraventricular hemorrhage (1.97) (P < 0.005). Length of stay increased with BPD (2.92) and NEC (surgical, 2.04; medical, 1.28) (P < 0.03). Total cost increased with surgical NEC (2.06), medical NEC (1.57), sepsis (1.43), and BPD (1.30) (P < 0.001). Conclusions:Propensity score-matched analysis demonstrates reduced mortality in premature/ELBW infants with SL for PDA. NEC and sepsis are predictors of mortality and resource utilization.

Exploring Animal Models That Resemble Idiopathic Pulmonary Fibrosis

Large multicenter clinical trials have led to two recently approved drugs for patients with idiopathic pulmonary fibrosis (IPF); yet, both of these therapies only slow disease progression and do not provide a definitive cure. Traditionally, preclinical trials have utilized mouse models of bleomycin (BLM)-induced pulmonary fibrosis—though several limitations prevent direct translation to human IPF. Spontaneous pulmonary fibrosis occurs in other animal species, including dogs, horses, donkeys, and cats. While the fibrotic lungs of these animals share many characteristics with lungs of patients with IPF, current veterinary classifications of fibrotic lung disease are not entirely equivalent. Additional studies that profile these examples of spontaneous fibroses in animals for similarities to human IPF should prove useful for both human and animal investigators. In the meantime, studies of BLM-induced fibrosis in aged male mice remain the most clinically relevant model for preclinical study for human IPF. Addressing issues such as time course of treatment, animal size and characteristics, clinically irrelevant treatment endpoints, and reproducibility of therapeutic outcomes will improve the current status of preclinical studies. Elucidating the mechanisms responsible for the development of fibrosis and disrepair associated with aging through a collaborative approach between researchers will promote the development of models that more accurately represent the realm of interstitial lung diseases in humans.

Pediatric sinonasal tumors in the United States: incidence and outcomes

BACKGROUND Sinonasal tumors in the pediatric population are exceedingly rare. MATERIALS AND METHODS Surveillance, Epidemiology, and End Results database was used to identify 250 cases of sinonasal malignancy in patients aged <20 y (1973-2010). Malignant histology codes were based on the International Classification of Disease for Oncology, third edition coding scheme. Incidence rates were adjusted to the 2000 U.S. population. Survival outcomes were plotted using the Kaplan-Meier method and compared with the log-rank test. All other analyses were performed using standard statistical methods. RESULTS Overall incidence was 0.052 per 100,000. Rhabdomyosarcoma had the highest incidence among histologic groups. Regional stage was the most common at diagnosis (59%). Overall survival at 5-y follow-up was 62.5%. Patients in age groups 1-4 and 15-19 y had the worst survival rates, as median survival was 205 and 104 mo, respectively. Distant metastases at the time of diagnosis signified a poor prognosis. These were associated with a 39-mo median survival. Survival improved during the study period, P=0.003. Gender, race, site of lesion, or histology did not appear to affect mortality. CONCLUSIONS Sinonasal tumors are rare in children and adolescents. Long-term survival is dependent on age and clinical stage at the time of diagnosis. Cancer-related surgery confers a survival advantage. Gender, race, and histologic type are not associated with mortality.

Initial hematocrit predicts the use of blood transfusion in the pediatric trauma patient

PURPOSE Initial hematocrit (Hct) is generally not considered a marker of acute blood loss because it is assumed that physiologic response of fluid conservation to hemorrhage is delayed. We challenged this idea by theorizing that admission Hct correlates with conventional signs of shock and predicts the use of blood transfusion during resuscitation of pediatric trauma patients. METHODS Data from 1928 pediatric admissions (<18 years) at a Level I trauma center (2000-2012) were compared using standard statistical analyses and logistic regression modeling to identify factors associated with blood transfusion during initial trauma resuscitation. RESULTS Overall mortality rate was 3.5%, with a transfusion rate of 10.7%. Factors significantly associated with transfusion were initial Hct, Glasgow Coma Score, base deficit, and injury severity score (all p<0.001). Initial Hct is a stronger predictor for transfusion (area under receiver operator curve (AUC: 0.728) compared to age-specific tachycardia (AUC: 0.689), age-specific hypotension (AUC: 0.673), and altered mental status (AUC: 0.654)). On multivariate analysis, initial Hct was an independent predictor (OR [95% CI]: 2.94 [1.56, 5.52]) along with hypotension (6.37 [2.95, 13.8]), base deficit (4.14 [1.38, 12.4]), and tachycardia (3.07 [1.62, 5.81]). CONCLUSIONS Initial Hct correlates significantly with conventional signs of shock and is a strong independent predictor for blood transfusion with better predictability than other clinical factors.

The effect of gun control laws on hospital admissions for children in the United States

BACKGROUND Gun control laws vary greatly between states within the United States. We hypothesized that states with strict gun laws have lower mortality and resource utilization rates from pediatric firearms-related injury admissions. METHODS Kids’ Inpatient Database (1997–2012) was searched for accidental (E922), self-inflicted (E955), assault (E965), legal intervention-related (E970), or undetermined circumstance (E985) firearm injuries. Patients were younger than 20 years and admitted for their injuries. Case incidence trends were examined for the study period. Propensity score–matched analyses were performed using 38 covariates to compare outcomes between states with strict or lenient gun control laws. RESULTS Overall, 38,424 cases were identified, with an overall mortality of 7%. Firearm injuries were most commonly assault (64%), followed by accidental (25%), undetermined circumstance (7%), or self-inflicted (3%). A small minority involved military-grade weapons (0.2%). Most cases occurred in lenient gun control states (48%), followed by strict (47%) and neutral (6%). On 1:1 propensity score–matched analysis, in-hospital mortality by case was higher in lenient (7.5%) versus strict (6.5%) states, p = 0.013. Lenient states had a proportionally higher rate of accidental (31%) and self-inflicted injury (4%) versus strict states (17% and 1.6%, respectively), p < 0.001. Assault-related injuries were proportionally lower in lenient (54%) versus strict (75%) states, p < 0.001. Military-grade weapons were more common in lenient (0.4%) versus strict (0.1%) states, p = 0.001. CONCLUSIONS These findings highlight the importance of legislative measures and their role in injury prevention, as firearm injuries are entirely avoidable mechanisms of injury. Lenient gun control contributes not only to worse outcomes per case, but also to a more significant and detrimental impact on public health. LEVEL OF EVIDENCE Epidemiologic study, level III.

Laparoscopic Ladd's procedure for superior mesenteric artery syndrome.

Superior mesenteric artery (SMA) syndrome is an uncommon condition where the third portion of the duodenum is compressed and obstructed between the SMA and the aorta. An otherwise healthy 17-year-old female presented with a 2-month history of postprandial abdominal pain and weight loss. Upper gastrointestinal (UGI) series demonstrated SMA obstruction of the third portion of the duodenum. Despite nasojejunal tube feedings over 4months with appropriate weight gain, symptoms continued and repeat UGI demonstrated persistent SMA syndrome. A laparoscopic Ladds procedure served as definitive treatment. The steps of the procedure include mobilization of the Ligament of Treitz, mobilization of the right colon, complete derotation of the duodenum, delivery of the small bowel to the right upper quadrant, and appendectomy. Following the procedure, a postoperative UGI showed complete resolution of SMA compression of the duodenum. The patient had an uneventful postoperative course with immediate resolution of symptoms. She was discharged home tolerating a regular diet.

Pediatric histiocytoses in the United States: incidence and outcomes

BACKGROUND Histiocytoses are rare disorders affecting the pediatric population. MATERIALS AND METHODS Surveillance, Epidemiology, and End Results database was searched for pediatric cases (<20 y old) of histiocytosis diagnosed between 1973 and 2010. Demographics, clinical characteristics, and survival outcomes were analyzed using standard statistical methods. Class I disease (Langerhans cell histiocytosis) and class III (malignant histiocytosis) were included in the data set. RESULTS A total of 828 cases were identified. Overall incidence was 0.142/100,000 persons per annum. Incidence was highest in younger children and those of Asian or Native American descent. Class III disease had a higher incidence versus class I. Adolescents tended to present with class III, whereas young children presented with class I. Disseminated disease was present in most cases of class III, whereas class I had more localized cases. Surgical excision was more likely to be performed in class I. Overall median survival was 349 mo. Patients 15-19 y old and children<1 y old had the worst outcomes. Class I had higher survival compared with class III, which had a median survival of 33 mo. Cases with hematologic spread carried the worst prognosis. Surgical excision conferred a survival advantage while radiation had no effect. Survival improved over the study period. Gender and race had no association with survival. CONCLUSIONS Class I disease had localized cases and showed benefit from surgical intervention. Class III disease had a higher incidence and was associated with disseminated disease and lower survival. Radiation therapy did not affect survival. Overall survival increased over the previous 40 y.