Gustavo A. Rubio

Allogeneic Human Mesenchymal Stem Cells in Patients With Idiopathic Pulmonary Fibrosis via Intravenous Delivery (AETHER): A Phase I Safety Clinical Trial

Background Despite Food and Drug Administration approval of 2 new drugs for idiopathic pulmonary fibrosis (IPF), curative therapies remain elusive and mortality remains high. Preclinical and clinical data support the safety of human mesenchymal stem cells as a potential novel therapy for this fatal condition. The Allogeneic Human Cells (hMSC) in patients with Idiopathic Pulmonary Fibrosis via Intravenous Delivery (AETHER) trial was the first study designed to evaluate the safety of a single infusion of bone marrow–derived mesenchymal stem cells in patients with idiopathic pulmonary fibrosis. Methods Nine patients with mild to moderate IPF were sequentially assigned to 1 of 3 cohorts and dosed with a single IV infusion of 20, 100, or 200 × 106 human bone marrow–derived mesenchymal stem cells per infusion from young, unrelated, men. All baseline patient data were reviewed by a multidisciplinary study team to ensure accurate diagnosis. The primary end point was the incidence (at week 4 postinfusion) of treatment‐emergent serious adverse events, defined as the composite of death, nonfatal pulmonary embolism, stroke, hospitalization for worsening dyspnea, and clinically significant laboratory test abnormalities. Safety was assessed until week 60 and additionally 28 days thereafter. Secondary efficacy end points were exploratory and measured disease progression. Results No treatment‐emergent serious adverse events were reported. Two nontreatment‐related deaths occurred because of progression of IPF (disease worsening and/or acute exacerbation). By 60 weeks postinfusion, there was a 3.0% mean decline in % predicted FVC and 5.4% mean decline in % predicted diffusing capacity of the lungs for carbon monoxide. Conclusions Data from this trial support the safety of a single infusion of human mesenchymal stem cells in patients with mild‐moderate IPF. Trial Registry ClinicalTrials.gov; No.: NCT02013700; URL: www.clinicaltrials.gov.

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.

Internet Usage Trends in Thoracic Surgery Patients and Their Caregivers

With trends toward increasing patient involvement in medical decision-making, decreasing clinic times, and the availability of the Internet, patients and their caregivers are increasingly researching cancer diagnoses online. It is essential for physicians to understand patient Internet usage as it relates to their own health education. Internet usage trends have been studied in various areas, but not in thoracic diseases. This prospective cohort study surveyed 337 thoracic surgery patients and their caregivers with both cancer and non-cancer diagnoses to examine their Internet usage trends. Cancer subjects were more likely to research their condition online if they were younger, had a higher income, had a higher education level, and were currently employed. Only age and income level were predictive for non-cancer subjects. Separately, cancer subjects were more likely to trust information found on the Internet if they had a higher education. Subjects were most likely to conduct research on a hospital website than other websites. These data will be helpful to thoracic surgeons who want to appropriately educate patients and their caregivers and direct them to reliable Internet sources. These data also illustrate the importance of developing trustworthy hospital websites with disease-specific information.

Estrogen receptor subtype expression and regulation is altered in papillary thyroid cancer after menopause

Background. Estrogen receptors can regulate growth in papillary thyroid cancer and may affect prognosis after menopause. This study examines changes of estrogen receptor subtype ratio expression in papillary thyroid cancer cell lines derived from pre‐ and postmenopausal women. Methods. Cells were harvested from papillary thyroid cancer and non‐papillary thyroid cancer thyroid tissue (control) from pre‐ (n = 9) and postmenopausal women (n = 11). Protein expression of estrogen receptor &agr;, estrogen receptor &bgr;, and phosphorylated extracellular signal‐regulated kinase and protein kinase B were analyzed. Matrix metalloproteinase‐2 activity was determined as a measure of tumor invasiveness. Mitochondrial retrograde signaling was altered with ethidium bromide to determine its effect on estrogen receptor &agr; protein expression. Results. Estrogen receptor &agr; expression was increased in postmenopausal papillary thyroid cancer cells compared with controls but was unchanged in premenopausal papillary thyroid cancer. Estrogen receptor &bgr; expression did not change in either group. Increased matrix metalloproteinase‐2 activity was observed only in postmenopausal papillary thyroid cancer. Premenopausal papillary thyroid cancer cells demonstrated increased extracellular signal‐regulated kinase and unchanged protein kinase B activation. Conversely, postmenopausal papillary thyroid cancer cells had decreased extracellular signal‐regulated kinase and increased protein kinase B activation. Ethidium bromide treatment resulted in increased estrogen receptor &agr; protein expression only in premenopausal papillary thyroid cancer cells. Conclusion. Increased estrogen receptor &agr; expression may be involved in papillary thyroid cancer aggressiveness after menopause. This process may be regulated by differential activation of intracellular pathways and differing sensitivities to mitochondrial signaling regulation.

Inhibition of Advanced Glycation End Products (AGEs) Accumulation by Pyridoxamine Modulates Glomerular and Mesangial Cell Estrogen Receptor α Expression in Aged Female Mice.

Age-related increases in oxidant stress (OS) play a role in regulation of estrogen receptor (ER) expression in the kidneys. In this study, we establish that in vivo 17β-estradiol (E2) replacement can no longer upregulate glomerular ER expression by 21 months of age in female mice (anestrous). We hypothesized that advanced glycation end product (AGE) accumulation, an important source of oxidant stress, contributes to these glomerular ER expression alterations. We treated 19-month old ovariectomized female mice with pyridoxamine (Pyr), a potent AGE inhibitor, in the presence or absence of E2 replacement. Glomerular ERα mRNA expression was upregulated in mice treated with both Pyr and E2 replacement and TGFβ mRNA expression decreased compared to controls. Histological sections of kidneys demonstrated decreased type IV collagen deposition in mice receiving Pyr and E2 compared to placebo control mice. In addition, anti-AGE defenses Sirtuin1 (SIRT1) and advanced glycation receptor 1 (AGER1) were also upregulated in glomeruli following treatment with Pyr and E2. Mesangial cells isolated from all groups of mice demonstrated similar ERα, SIRT1, and AGER1 expression changes to those of whole glomeruli. To demonstrate that AGE accumulation contributes to the observed age-related changes in the glomeruli of aged female mice, we treated mesangial cells from young female mice with AGE-BSA and found similar downregulation of ERα, SIRT1, and AGER1 expression. These results suggest that inhibition of intracellular AGE accumulation with pyridoxamine may protect glomeruli against age-related oxidant stress by preventing an increase of TGFβ production and by regulation of the estrogen receptor.

Mesenchymal stromal cells prevent bleomycin-induced lung and skin fibrosis in aged mice and restore wound healing

Fibrosis can develop in nearly any tissue leading to a wide range of chronic fibrotic diseases. However, current treatment options are limited. In this study, we utilized an established aged mouse model of bleomycin‐induced lung fibrosis (BLM) to test our hypothesis that fibrosis may develop simultaneously in multiple organs by evaluating skin fibrosis and wound healing. Fibrosis was induced in lung in aged (18–22‐month‐old) C57BL/6 male mice by intratracheal BLM administration. Allogeneic adipose‐derived mesenchymal stromal cells (ASCs) or saline were injected intravenously 24 hr after BLM administration. Full thickness 8‐mm punch wounds were performed 7 days later to study potential systemic anti‐fibrotic and wound healing effects of intravenously delivered ASCs. Mice developed lung and skin fibrosis as well as delayed wound closure. Moreover, we observed similar changes in the expression of known pro‐fibrotic factors in both lung and skin wound tissue, including miR‐199 and protein expression of its corresponding target, caveolin‐1, as well as phosphorylation of protein kinase B. Importantly, ASC‐treated mice exhibited attenuation of BLM‐induced lung and skin fibrosis and accelerated wound healing, suggesting that ASCs may prime injured tissues and prevent end‐organ fibrosis.

Incidence and Outcomes of Dermatofibrosarcoma Protuberans in the US Pediatric Population.

Background: Dermatofibrosarcoma protuberans (DFSP) is a low-grade soft tissue sarcoma. In the pediatric population, DFSP is exceedingly rare. Aim of this study was to describe the epidemiology and clinical outcomes in a large pediatric cohort. Methods: Surveillance, Epidemiology, and End Results (SEER) database (1973–2010) was analyzed for all patients with dermatofibrosarcoma occurring in patients <20 years of age. Data were extracted based on age, gender, race, anatomic site, histology, stage, treatment modalities, and survival. Incidence rates were standardized to the 2000 US population. Results: A total of 451 patients were identified. Overall annual incidence was 0.10 per 100,000. Incidence was highest among black children and adolescents (ages 15 to 19 years). Trunk was most common site, followed by extremities. Head and neck region was least common site (P < 0.05). Majority (54%) of patients presented with localized disease. Overall, 95% underwent surgery. Only 2.2% were treated with perioperative radiation therapy. Overall prognosis was favorable with 5-year overall survival (OS) of 100%, 15-year OS of 98%, and 30-year OS of 97%. Median survival was 117 months. Male patients had lower 15- and 30-year OS compared with females (P < 0.05). Conclusion: Pediatric DFSP has lower incidence but similar clinical characteristics to adults. Incidence is higher in black children and in the trunk region. While prognosis is favorable, male sex is associated with decreased OS.

Lung Diseases of the Elderly: Cellular Mechanisms

Natural lung aging is characterized by molecular and cellular changes in multiple lung cell populations. These changes include shorter telomeres, increased expression of cellular senescence markers, increased DNA damage, oxidative stress, apoptosis, and stem cell exhaustion. Aging, combined with the loss of protective repair processes, correlates with the development and incidence of chronic respiratory diseases, including idiopathic pulmonary fibrosis and chronic obstructive pulmonary disease. Ultimately, it is the interplay of age-related changes in biology and the subsequent responses to environmental exposures that largely define the physiology and clinical course of the aging lung.

What Should Be Chronic: The Animal, the Model, or Both?

The systematic review of mesenchymal stromal cell (MSC) therapy in pulmonary fibrosis by Srour and Thébaud published in a recent issue of Stem Cells Translational Medicine is critically reviewed; Rubio et al. suggest that bleomycin-induced lung injury in aged mice studied over time is a more clinically applicable model for human idiopathic pulmonary fibrosis.

Incidence and outcomes of pediatric extremity melanoma: A propensity score matched SEER study

BACKGROUND There is a paucity of literature on treatment of melanoma in children with surgical management extrapolated from adult experience. The incidence and clinical outcomes of pediatric extremity melanoma were studied. METHODS SEER registry was analyzed between 1973 and 2010 for patients <20years old with extremity melanoma. Multivariate and propensity-score matched analyses were performed to identify independent predictors of survival. RESULTS Overall, 917 patients were identified with an age-adjusted incidence of 0.2/100,000 persons, annual percent change 0.96. Most had localized disease (77%), histology revealing melanoma-not otherwise specified (52%). Surgical procedures performed included wide local excision (50%), excisional biopsy (32%), lymphadenectomy (LA) (28%), and sentinel lymph node biopsy (SLNB) (15%). Overall, 30-year disease specific mortality was 7% with lower survival for extremity melanoma (90%), males (89%), nodular histology (69%), and distant disease (36%) (all P<0.05). Post-treatment multivariate analysis revealed localized disease (HR 9.76; P=0.006) as an independent prognosticator of survival; earlier diagnostic years 1988-1999 (HR 2.606; P=0.017) were a negative prognosticator of survival. Propensity-score matched analysis found no difference in survival between SLNB/LA vs no sampling for regional/distant disease. CONCLUSIONS Pediatric extremity melanoma in SEER demonstrate no survival advantage between children undergoing sampling procedures vs no sampling for regional/distant disease. TYPE OF STUDY Retrospective, prognostic study. LEVEL OF EVIDENCE III.