Liane Miller

Gene Expression Profile Identifies Tyrosine Kinase c-Met as a Targetable Mediator of Antiangiogenic Therapy Resistance

Purpose: To identify mediators of glioblastoma antiangiogenic therapy resistance and target these mediators in xenografts. Experimental Design: We conducted microarray analysis comparing bevacizumab-resistant glioblastomas (BRG) with pretreatment tumors from the same patients. We established novel xenograft models of antiangiogenic therapy resistance to target candidate resistance mediator(s). Results: BRG microarray analysis revealed upregulation versus pretreatment of receptor tyrosine kinase c-Met, which underwent further investigation because of its prior biologic plausibility as a bevacizumab resistance mediator. BRGs exhibited increased hypoxia versus pretreatment in a manner correlating with their c-Met upregulation, increased c-Met phosphorylation, and increased phosphorylation of c-Met–activated focal adhesion kinase and STAT3. We developed 2 novel xenograft models of antiangiogenic therapy resistance. In the first model, serial bevacizumab treatment of an initially responsive xenograft generated a xenograft with acquired bevacizumab resistance, which exhibited upregulated c-Met expression versus pretreatment. In the second model, a BRG-derived xenograft maintained refractoriness to the MRI tumor vasculature alterations and survival-promoting effects of bevacizumab. Growth of this BRG-derived xenograft was inhibited by a c-Met inhibitor. Transducing these xenograft cells with c-Met short hairpin RNA inhibited their invasion and survival in hypoxia, disrupted their mesenchymal morphology, and converted them from bevacizumab-resistant to bevacizumab-responsive. Engineering bevacizumab-responsive cells to express constitutively active c-Met caused these cells to form bevacizumab-resistant xenografts. Conclusion: These findings support the role of c-Met in survival in hypoxia and invasion, features associated with antiangiogenic therapy resistance, and growth and therapeutic resistance of xenografts resistant to antiangiogenic therapy. Therapeutically targeting c-Met could prevent or overcome antiangiogenic therapy resistance. Clin Cancer Res; 19(7); 1773–83. ©2012 AACR.

Factors predicting postoperative hyponatremia and efficacy of hyponatremia management strategies after more than 1000 pituitary operations

OBJECT Syndrome of inappropriate antidiuretic hormone secretion-induced hyponatremia is a common morbidity after pituitary surgery that can be profoundly symptomatic and cause costly readmissions. The authors calculated the frequency of postoperative hyponatremia after 1045 consecutive operations and determined the efficacy of interventions correcting hyponatremia. METHODS The authors performed a retrospective review of 1045 consecutive pituitary surgeries in the first 946 patients treated since forming a dedicated pituitary center 5 years ago. Patients underwent preoperative and daily inpatient sodium checks, with outpatient checks as needed. RESULTS Thirty-two patients presented with hyponatremia; 41% of these patients were symptomatic. Postoperative hyponatremia occurred after 165 operations (16%) a mean of 4 days after surgery (range 0-28 days); 19% of operations leading to postoperative hyponatremia were associated with postoperative symptoms (38% involved dizziness and 29% involved nausea/vomiting) and 15% involved readmission for a mean of 5 days (range 1-20 days). In a multivariate analysis including lesion size, age, sex, number of prior pituitary surgeries, surgical approach, pathology, lesion location, and preoperative hypopituitarism, only preoperative hypopituitarism predicted postoperative hyponatremia (p = 0.006). Of patients with preoperative hyponatremia, 59% underwent medical correction preoperatively and 56% had persistent postoperative hyponatremia. The mean correction rates were 0.4 mEq/L/hr (no treatment; n = 112), 0.5 mEq/L/hr (free water restriction; n = 24), 0.7 mEq/L/hr (salt tablets; n = 14), 0.3 mEq/L/hr (3% saline; n = 20), 0.7 mEq/L/hr (intravenous vasopressin receptor antagonist Vaprisol; n = 22), and 1.2 mEq/L/hr (oral vasopressin receptor antagonist tolvaptan; n = 9) (p = 0.002, ANOVA). While some patients received more than 1 treatment, correction rates were only recorded when a treatment was given alone. CONCLUSIONS After 1045 pituitary operations, postoperative hyponatremia was associated exclusively with preoperative hypopituitarism and was most efficiently managed with oral tolvaptan, with several interventions insignificantly different from no treatment. Promptly identifying hyponatremia in high-risk patients and management with agents like tolvaptan can improve safety and decrease readmission. For readmitted patients with severely symptomatic hyponatremia, the intravenous vasopressin receptor antagonist Vaprisol is another treatment option.

Economic Impact of Revision Surgery for Proximal Junctional Failure After Adult Spinal Deformity Surgery: A Cost Analysis of 57 Operations in a 10-year Experience at a Major Deformity Center.

Study Design. Retrospective cohort analysis. Objective. To evaluate the economic impact of revision surgery for proximal junctional failures (PJF) after thoracolumbar fusions for adult spinal deformity (ASD). Summary of Background Data. PJF after fusions for ASD is a major cause of disability. Although clinical sequelae are described, PJF-revision operation costs are incompletely defined. Methods. Consecutive adults who underwent thoracolumbar fusions for ASD (August, 2003 to January, 2013) were evaluated. Inclusion criteria include construct from pelvis to L2 or above and minimum 6 months follow-up after the index ASD operation. Direct costs (surgical supplies/implants, room/care, pharmacy, services) were identified from medical billing data and calculated for index ASD operations and subsequent surgeries for PJF. Not included in direct cost data were indirect costs, charges, surgeon fees, or revision operations for indications other than PJF (i.e., pseudarthrosis). Patients were compared based on the constructs upper-instrumented vertebra: upper thoracic (UT: T1–6) versus thoracolumbar junction (TLjxn: T9-L2). Results. Of 501 patients, 382 met inclusion criteria. Fifty-one patients [UT:14; TLjxn: 40 at index; average follow-up 32.6 months (6–92 months)] had revisions for PJF, which summed to

Incidence of headache as a presenting complaint in over 1000 patients with sellar lesions and factors predicting postoperative improvement.

3.2 million total direct cost. Average direct cost of index operations for the cohort (

Improved versus worsened endocrine function after transsphenoidal surgery for nonfunctional pituitary adenomas: rate, time course, and radiological analysis.

68,294) was significantly greater than PJF-revisions (

Skull Base Chordomas: Clinical Features, Prognostic Factors, and Therapeutics

55,547). Compared with TLjxn, UT had a significantly higher average cost for index operations (

Acute Fixation of Type IV and V Acromioclavicular Separations: An Internal Splint Technique

79,860 vs.

Abstract 1610: Serial treatment-transplant xenograft model of Bevacizumab-resistance reveals temporal induction of markers associated with disease progression.

65,868). However, PJF-revision cases were similar in average cost (UT:

Morbidity of repeat transsphenoidal surgery assessed in more than 1000 operations

60,103; TLjxn:

Rate and time course of improvement in endocrine function after more than 1000 pituitary operations.

53,920; P = 0.09). Costs of PJF amounted to an additional 12.1% of the total index surgical cost in 382 patients. Conclusion. Revision operations for PJF after long thoracolumbar fusions for ASD are associated with an average direct cost of