Mace T.A.,Divisions of Medical Oncology |
Ameen Z.,Divisions of Medical Oncology |
Mair M.,Divisions of Medical Oncology |
Young G.S.,Arthur G James Cancer Hospital And Richard J Solove Research Institute |
And 4 more authors.
Cancer Research | Year: 2013
Pancreatic stellate cells (PSC) are a subset of pancreatic cancer-associated fibroblasts. These cells provide prosurvival signals to tumors; however, little is known regarding their interactions with immune cells within the tumor microenvironment. We hypothesized that factors produced by human PSC could enhance myeloid-derived suppressor cell (MDSC) differentiation and function, which promotes an immunosuppressive microenvironment. Primary PSC cell lines (n 1/4 7) were generated from human specimens and phenotypically confirmed via expression of vimentin, a-smooth muscle actin (a-SMA), and glial fibrillary acidic protein (GFAP). Luminex analysis indicated that PSC but not human fetal primary pancreatic fibroblast cells (HPF; negative controls) produced MDSC-promoting cytokines [interleukin (IL-6), VEGF, macrophage colony-stimulating factor (M-CSF) ] and chemokines (SDF-1, MCP-1). Culture of peripheral blood mononuclear cells [peripheral blood mononuclear cell (PBMC), n 1/4 3 donors] with PSC supernatants or IL-6/granulocyte macrophage colony-stimulating factor (GM-CSF; positive control) for 7 days promoted PBMC differentiation into an MDSC (CD11b+CD33+) phenotype and a subpopulation of polymorphonuclear CD11b+CD33+CD15+ cells. The resulting CD11b+CD33+ cells functionally suppressed autologous T-lymphocyte proliferation. In contrast, supernatants from HPF did not induce an MDSC phenotype in PBMCs. Culture of normal PBMCs with PSC supernatants led to STAT3 but not STAT1 or STAT5 phosphorylation. IL-6 was an important mediator as its neutralization inhibited PSC supernatant-mediated STAT3 phosphorylation and MDSC differentiation. Finally, the FLLL32 STAT3 inhibitor abrogated PSC supernatant-mediated MDSC differentiation, PSC viability, and reduced autocrine IL-6 production indicating these processes are STAT3 dependent. These results identify a novel role for PSC in driving immune escape in pancreatic cancer and extend the evidence that STAT3 acts as a driver of stromal immunosuppression to enhance its interest as a therapeutic target. Cancer Res; 73(10); 3007-18. © 2013 AACR.
Katyal A.,Critical Care & Sleep Medicine |
Neurocritical Care | Year: 2016
Background: Spontaneous pneumocephalus in the nontraumatic setting is distinctly unusual. Pneumocephalus from central nervous system infection with Clostridium septicum has been rarely reported, and more commonly reflects a later stage of abscess formation. We present an unusual case of invasive C. septicum infection without an associated diagnosed malignancy presenting with rapidly progressive CNS pathology and resultant early pneumocephalus. Methods: Medical records, radiologic imaging, and microbiological specimens of a case were reviewed. Results: A 66-year-old male presented with a history of two witnessed generalized tonic–clonic seizures on awakening. He was found unresponsive at the scene by paramedics and subsequently intubated. There was no reported antecedent symptomatology, such as headache, fever, chills, focal weakness, and speech or gait disturbances. Medical history was remarkable only for diet-controlled hypertension. Computed tomography (CT) head imaging revealed an abnormal right parietal hypodensity. The patient was evaluated per the acute stroke protocol but was not deemed a candidate for intervention or thrombolytic therapy given the uncertainty of his clinical presentation; intravenous antibiotics were administered for possible sepsis. Follow-up CT imaging of the head performed 8 h later revealed right parieto-temporal pneumocephalus with extensive cerebral edema and effacement of basilar cisterns. Neurosurgical intervention was not deemed appropriate given the catastrophic nature of his injury and the patient subsequently expired 14 h after presentation. Blood cultures grew gram-positive rods in three of four bottles identified as C. septicum. Conclusions: Clostridium septicum is an uncommon and often fatal cause of nontraumatic pneumocephalus. This underscores the need for a high index of clinical suspicion in cases with unexplained pneumocephalus, as early diagnosis remains the key to survival. In survivors of C. septicum infection, subsequent colonoscopy should be considered to exclude undiagnosed or occult gastrointestinal malignancy. © 2015, Springer Science+Business Media New York.
Mayo P.H.,Long Island Jewish Medical Center |
Hegde A.,Pulmonary |
Eisen L.A.,Montefiore Medical Center |
Kory P.,Beth Israel Deaconess Medical Center |
Doelken P.,Medical University of South Carolina
Journal of Intensive Care Medicine | Year: 2011
Objective: To assess the results of a quality improvement (QI) project designed to improve safety of emergency endotracheal intubation (EEI). Design: Single center prospective observational. Setting: 16-bed intensive care unit. Participants: Nine pulmonary/critical care fellows. Interventions: For 3 years, EEI performed by the medical intensive care unit team were analyzed to identify interventions that would improve quality of the procedure. By segmental process analysis, the procedure of EEI was subjected to iterative change. Major components of process improvement were development of a combined team approach, a mandatory checklist, use of crew resource management (CRM) tactics, and postevent debriefing. Quality analysis and improvement included training of fellows using scenario-based training (SBT) with computerized patient simulator (CPS) to improve mechanical skills of intubation and team leadership. Fellows received 15 sessions of SBT with CPS using a combined checklist and team approach before assuming team leadership position during real-life EEI. Measurements: For a 10-month period, fellows carried digital voice recorders to EEI; which, when combined with recording of continuous oximetry and BP monitoring were used to assess the quality of EEI. Main Results: 128 EEI were performed of which 101 had full data recorded. Complications were 14% severe hypoxemia (<80% saturation), 6% severe hypotension (SBP<70 mm Hg), 1% death, 20% difficult EEI (≥3 attempts), 11% esophageal intubations, 2% aspiration, and 1% dental injury; 62% EEI were successfully achieved on first attempt, 11% required >3 attempts. Conclusions: EEI may be performed by pulmonary/critical medicine (PCCM) fellows with safety comparable to that described in other studies on EEI. Important parts of the program included the use of formal iterative QI approach, the use of intensive SBT with CPS, basic CRM, a comprehensive checklist, and a combined team approach. A key benefit of the program was to make the process of EEI fully transparent for ongoing quality and safety improvement. © SAGE Publications 2011.
Current Respiratory Medicine Reviews | Year: 2010
Purpose of Review: This review focuses on the pathophysiology of proximal airway infection in the ventilated patient. Ventilator-associated tracheobronchitis (VAT) is increasingly recognized as an important entity not only as an essential step in the pathway from oral colonization to deep lung infection but also as an infection associated with its own morbidity. Recent Findings: Multiple recent clinical trials have focused on the effects of new devices and treatment protocols on the morbidity associated with the progression of airway colonization to VAT or with the progression of VAT to VAP. Continuous subglottic secretion suctioning (CASS), innovative types of endotracheal tubes, and targeted therapy for VAT in recent investigations have shown promise in improving clinical outcomes in the critically ill patient. However, even with diligent attention to all the modifiable risk factors for respiratory infection, complete elimination of VAT and VAP remains unlikely. As long as a patient requires an endotracheal tube which disturbs airway integrity, host defenses will be impaired, and resistant virulent organisms which result from our liberal use of systemic antibiotics will continue to challenge critical care specialists. Summary: This review will focus on: 1) the current understanding of the pathogenesis of VAT, 2) modifiable risk factors, and 3) new approaches to treatment and bacterial resistance challenges. © 2010 Bentham Science Publishers Ltd.
Clinics in Chest Medicine | Year: 2011
This review summarizes recent clinical data examining the use of aerosolized antimicrobial therapy for the treatment of respiratory tract infections in mechanically ventilated patients in the intensive care unit. Aerosolized antibiotics provide high concentrations of drug in the lung without the systemic toxicity associated with the intravenous antibiotics. First introduced in the 1960s as a treatment of tracheobronchitis and bronchopneumonia caused by Pseudomonas aeruginosa, now, more than 40 years later, there is a resurgence of interest in using this mode of delivery as a primary therapy for ventilator-associated tracheobronchitis and an adjunctive therapy for ventilator-associated pneumonia. © 2011 Elsevier Inc.