Subject(s)
Giant Cell Arteritis/diagnosis , Intracranial Aneurysm/diagnosis , Oculomotor Nerve Diseases/diagnosis , Temporal Arteries/pathology , Aged , Blepharoptosis/diagnosis , C-Reactive Protein/metabolism , Computed Tomography Angiography , Diplopia/diagnosis , Female , Giant Cell Arteritis/drug therapy , Glucocorticoids/administration & dosage , Humans , Intracranial Aneurysm/drug therapy , Intracranial Aneurysm/physiopathology , Prednisone/administration & dosage , Temporal Arteries/drug effects , Visual AcuityABSTRACT
Patients with acute myeloid leukemia (AML) often relapse after initial therapy because of persistence of leukemic stem cells that frequently express the IL-3 receptor alpha chain CD123. Natural killer (NK) cell-based therapeutic strategies for AML show promise and we explore the NK cell lines, NK-92 and CD16+ NK-92, as a treatment for AML. NK-92 has been tested in phase I clinical trials with minimal toxicity; irradiation prior to infusion prevents risk of engraftment. The CD16 negative NK-92 parental line was genetically modified to express the high affinity Fc gamma receptor, enabling antibody-dependent cell-mediated cytotoxicity, which we utilized in combination with an anti-CD123 antibody to target leukemic stem cells. NK-92 was preferentially cytotoxic against leukemic stem and progenitor cells compared with bulk leukemia in in vitro assays, while CD16+ NK-92 in combination with an anti-CD123 mAb mediated antibody-dependent cell-mediated cytotoxicity against CD123+ leukemic targets. Furthermore, NK-92 infusions (with or without prior irradiation) improved survival in a primary AML xenograft model. Mice xenografted with primary human AML cells had a superior survival when treated with irradiated CD16+NK-92 cells and an anti-CD123 monoclonal antibody (7G3) versus treatment with irradiated CD16+NK-92 cells combined with an isotype control antibody. In this proof-of-principle study, we show for the first time that a CD16+NK-92 cell line combined with an antibody that targets a leukemic stem cell antigen can lead to improved survival in a relevant pre-clinical model of AML.
Subject(s)
Antineoplastic Agents, Immunological/pharmacology , Interleukin-3 Receptor alpha Subunit/antagonists & inhibitors , Leukemia, Myeloid, Acute/drug therapy , Neoplasm Proteins/antagonists & inhibitors , Receptors, IgG/antagonists & inhibitors , Animals , GPI-Linked Proteins/antagonists & inhibitors , GPI-Linked Proteins/metabolism , Humans , Interleukin-3 Receptor alpha Subunit/metabolism , K562 Cells , Leukemia, Myeloid, Acute/metabolism , Leukemia, Myeloid, Acute/pathology , Mice , Mice, Inbred NOD , Mice, SCID , Neoplasm Proteins/metabolism , Receptors, IgG/metabolism , Xenograft Model Antitumor AssaysABSTRACT
BACKGROUND: Predictive models of prolonged air leak have relied on information not always available preoperatively (eg, extent of resection, pleural adhesions). Our objective was to construct a model to identify patients at increased risk of prolonged air leak using preoperative factors exclusively. METHODS: From 2012 to 2014, data on consecutive patients undergoing pulmonary resection were collected prospectively. Prolonged air leak was defined as lasting longer than 7 days and requiring hospitalization. Factors associated with the primary outcome (p < 0.2) were included in a multivariate model. Regression coefficients were used to develop a weighted risk score for prolonged air leak. RESULTS: Of 225 patients, 8% (18/225) experienced a prolonged air leak. Male gender (p = 0.08), smoking history (p = 0.03), body mass index (BMI) 25 or below (p < 0.01), Medical Research Council (MRC) dyspnea score above 1 (p = 0.06), and diffusion capacity for carbon monoxide below 80% (Dlco) (p = 0.01) were selected for inclusion in the final model. Weighted scores were male gender (1 point), BMI 25 or below (0.5 point), smoker (2 points), Dlco% below 80% (2 points), and MRC dyspnea score above 1 (1 point). The area under the receiver operating characteristic curve was 0.8 (95% confidence interval [CI] = 0.7 to 0.9]. An air leak score above 4 points offered the best combination of sensitivity (83% [95% CI = 58 to 96]) and specificity (65% [95% CI = 58 to 71]). CONCLUSIONS: A subgroup of lung resection patients at higher risk for a prolonged air leak can be effectively identified with the use of widely available, preoperative factors. The proposed scoring system is simple, is clinically relevant to the informed consent, and allows preoperative patient selection for interventions to reduce the risk of prolonged air leak.
Subject(s)
Anastomotic Leak/diagnosis , Bronchi/surgery , Lung Neoplasms/surgery , Pleural Diseases/diagnosis , Pneumonectomy/adverse effects , Risk Assessment , Aged , Anastomosis, Surgical/adverse effects , Anastomotic Leak/epidemiology , Female , Follow-Up Studies , Humans , Incidence , Male , Middle Aged , Ontario/epidemiology , Pleural Diseases/epidemiology , ROC Curve , Retrospective Studies , Risk Factors , Time FactorsABSTRACT
OBJECTIVE: An unclear aspect of digital pleural drainage technology is whether it can benefit all lung resection patients or only those who have a postoperative air leak. The aim of this study was to evaluate the impact of digital pleural drainage on time to chest tube removal and length of hospitalization, taking into consideration postoperative air leak status. METHODS: A single-center, randomized, controlled, open-label, parallel-group trial was conducted. On postoperative day 1, stratification according to air leak status was performed by 2 independent, blinded observers. Patients were randomized to a water-sealed, pleural drainage device (analog) or to a digital device (digital). RESULTS: In both air leak groups (no air leak = 87; air leak = 85), patient factors and operative details were comparable. In the no air leak group, the difference in median chest tube drainage between analog and digital randomization arms was not statistically significant (3 days vs 2.9 days; P = .05). Median length of stay was also comparable in that group (analog = 4.3 days; digital = 4 days; P = .09). In patients with an air leak, similar findings were observed for chest tube duration (analog = 5.6 days; digital = 4.9 days; P = .11) and length of stay (analog = 6.2 days; digital = 6.2 days; P = .36). Chest tube clamping trials were significantly reduced in the digital arm of the air leak absent (0% vs 16%; P = .01) and air leak present groups (23% vs 50%; P = .01). CONCLUSIONS: Although digital devices decreased tube clamping trials, the impact on duration of chest tube drainage and hospital stay was not statistically significant, even after stratifying by postoperative air leak status.
