Background

There is no standard method for the surgical treatment of acromioclavicular (AC) joint separations. Current techniques have associated complications, including need for device removal, coracoid fracture, and inadequate reduction.

Purpose

To evaluate the clinical outcomes of an internal splint technique without graft augmentation or rigid fixation to treat acute Rockwood type IV and V AC joint injuries.

Study design

Case series; Level of evidence, 4.

Methods

A retrospective analysis was performed of 26 patients who underwent a novel internal splint fixation technique between 2011 and 2016. Patients had type IV (n = 2) and type V (n = 24) acute AC separations. The mean time to surgery was 13.7 days (range, 1-28 days). The surgical technique included an open approach with coracoclavicular suture and tape fixation and AC suture fixation. Range of motion, strength, and radiographs were evaluated after surgery. Patient follow-up included the DASH (Disabilities of the Arm, Shoulder and Hand) questionnaire at a mean 3.3 years postoperatively (range, 6 months-8.6 years). DASH questionnaires were obtained for all patients via email. Patients were also surveyed on cosmetic appearance and willingness to undergo the operation again.

Results

All patients regained full strength and range of motion following surgery. All postoperative radiographs demonstrated well-maintained reduction of the AC joint. The mean DASH score was 3.4 at final follow-up, and 23 of 26 respondents were satisfied with their postoperative shoulder appearance. There were no reoperations, and all patients stated that they would have the operation again given the same circumstances.

Conclusion

The results of this study demonstrate a reliable new technique for acute fixation of type IV or V AC joint injuries via an internal splint construct. This technique enables reduction in the coronal and sagittal planes without the need for graft augmentation or a rigid implant, allowing healing of the coracoclavicular and AC ligaments.

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.