EGFR ligand shifts the role of EGFR from oncogene to tumour suppressor in EGFR-amplified glioblastoma by suppressing invasion through BIN3 upregulation.

The epidermal growth factor receptor (EGFR) is a prime oncogene that is frequently amplified in glioblastomas. Here we demonstrate a new tumour-suppressive function of EGFR in EGFR-amplified glioblastomas regulated by EGFR ligands. Constitutive EGFR signalling promotes invasion via activation of a TAB1-TAK1-NF-κB-EMP1 pathway, resulting in large tumours and decreased survival in orthotopic models. Ligand-activated EGFR promotes proliferation and surprisingly suppresses invasion by upregulating BIN3, which inhibits a DOCK7-regulated Rho GTPase pathway, resulting in small hyperproliferating non-invasive tumours and improved survival. Data from The Cancer Genome Atlas reveal that in EGFR-amplified glioblastomas, a low level of EGFR ligands confers a worse prognosis, whereas a high level of EGFR ligands confers an improved prognosis. Thus, increased EGFR ligand levels shift the role of EGFR from oncogene to tumour suppressor in EGFR-amplified glioblastomas by suppressing invasion. The tumour-suppressive function of EGFR can be activated therapeutically using tofacitinib, which suppresses invasion by increasing EGFR ligand levels and upregulating BIN3.

Postoperative Care Pathways Following Lumbar Total Disc Replacement: Results of a Modified Delphi Approach.

STUDY DESIGN: A modified Delphi method was used to establish consensus. Subject matter experts were invited to participate as the expert panel. Best practice statements were distributed to the panel. Panel members were asked to mark "agree" or "disagree" after a series of statements during several rounds until either consensus could be obtained or the practice method was deemed unable to achieve consensus. OBJECTIVE: Lumbar total disc replacement (TDR) is acknowledged as an alternative to spinal fusion in appropriately selected patients. There is a lack of unanimity on the appropriate postoperative patient protocols and rehabilitation expectations for the procedure. The long-term viability of Lumbar TDR, further adoption in the community setting and specific patient outcomes are contingent on the existence of appropriate postoperative recovery programs. SUMMARY OF BACKGROUND DATA: Currently there are no established methods for postoperative care following lumbar TDR. Establishing a postoperative clinical pathway algorithm may improve patient outcomes with respect to lumbar TDR. METHOD: A lumbar TDR expert panel of 22 spine surgeons employed a modified Delphi method to drive consensus on postoperative care following single-level Lumbar TDR. The panel first reviewed literature and guidelines relevant to postoperative care following lumbar TDR. Panel members considered 21 survey questions intended to determine "standard-practice" postoperative care recommendations for patients who have undergone lumbar TDR for the initial recovery phase (0-4 wk) and rehabilitation (4-20 wk). Each panel member participated in a round of anonymous voting followed by a group discussion. Consensus was defined as 80% agreement or higher among the respondents. RESULTS: Consensus was achieved in 11 of the 21 survey questions. There was a high degree of consensus around the key goals for both the initial recovery and rehabilitation phases, ceased use of narcotics for pain management by 4 weeks postoperative, unrestricted walking immediately following surgery, timelines for physical therapy (within 2-4 wk) and return to work based on level of activity (as early as 1 wk postoperative). Lack of agreement included the use of back bracing and timing of postoperative visits. Generally, panel members felt that patient expectations regarding return to function were different following lumbar TDR versus fusion and warrant further study. CONCLUSION: Surgeon and patient alignment around postoperative expectations may significantly affect the long-term results of lumbar TDR. This surgeon consensus study found agreement for immediate postoperative ambulation, rapid reduction in opioids within the first month, and early return to work. When expectations are appropriately set with patients preoperatively, both provider and patient have shared goals in the return-to-function process. LEVEL OF EVIDENCE: 5.

Intradural Juvenile Xanthogranuloma with Involvement of Multiple Nerve Roots: A Case Report and Review of the Literature.

BACKGROUND: Juvenile xanthogranuloma (JXG) is a rare, non-Langerhans cell histiocytic disorder that primarily presents as multiple cutaneous lesions in young males. Solitary lesions in the spinal column are an especially rare presentation of this disease, and central nervous system involvement can portend a poor prognosis. We report an unusual case of an adult woman with an unresectable JXG of the lumbar spine. A review of the reported cases of thoracolumbar JXG and the current data regarding diagnosis and treatment are presented. CASE DESCRIPTION: A 28-year-old woman presented with back pain and worsening lower extremity pain, numbness, and weakness. Magnetic resonance imaging demonstrated an enhancing lumbar mass. However, at surgery, no discrete mass was identified. Multiple roots were grossly enlarged, and electrical stimulation identified the L4 root with the most abnormal findings. Despite an attempt at debulking, most of the mass could not be safely removed. The patient experienced incomplete improvement of the symptoms postoperatively but elected to forgo chemotherapy. The 3-month follow-up imaging study showed active lumbar spinal disease, and imaging and follow-up examinations at 27 months revealed no changes. Her symptoms were satisfactorily controlled with conservative therapy. CONCLUSIONS: JXG of the spine is a rare disease with nonspecific clinical and radiographic findings that can make it difficult to diagnose and dictates the use of immunohistochemical staining. If possible, total surgical resection will offer the best outcomes; however, other modalities such as chemotherapy can be viable alternatives or adjuvant modalities.

Solitary recurrence of castration-resistant prostate cancer with low or undetectable levels of prostate specific antigen salvaged with local ablative radiation therapy: A case report.

Prostate cancer recurrences are usually first detected by increased levels of prostate specific antigen (PSA), and systemic therapy is often initiated if distant metastasis is confirmed. However, low or nearly undetectable levels of PSA in the modern era of ultrasensitive PSA assay may be difficult to interpret in patients with a history of prostate cancer. Deciding whether to initiate additional systemic therapy in limited indolent metastatic disease while balancing the quality of life of the patient and ensuring the oncologic control of the disease may be challenging. In the present study, the case of a biopsy-confirmed solitary spine recurrence of prostate cancer with nearly undetectable but persistent levels of PSA (0.05 ng/ml) is reported. Treatment of the recurrence with local ablative radiotherapy improved the pain experienced by the patient, and reduced his levels of PSA to undetectable limits (<0.05 ng/ml). Repeated imaging analysis, PSA assay and clinical assessment demonstrated durable control of the disease without the requirement for additional systemic treatments. The present case highlighted the importance of initiating appropriate work-up according to the clinical scenario. Local treatment for solitary or oligometastatic recurrence of prostate cancer may enhance the effectiveness of current therapeutic strategies and benefit certain patients.

Ligand-Independent EGFR Signaling.

Constitutive activation of the EGFR is common in cancer due to EGFR wild-type (EGFRwt) overexpression or the presence of mutant EGFR. Signaling by constitutively active NSCLC EGFR mutants or the EGFRvIII mutant in glioblastoma has been studied intensively and the downstream signals are known. Normally, the EGFRwt is activated when it is exposed to ligand, resulting in activation of canonical signals such as ERK and Akt. The EGFRwt also becomes tyrosine phosphorylated and constitutively activated without ligand when it is overexpressed, but downstream signals are unclear. Recent studies have identified a noncanonical form of signaling triggered by EGFRwt exclusively in the absence of ligand that does not involve ERK or Akt activation but, instead, results in activation of the transcription factor IRF3. The addition of ligand turns off IRF3-dependent transcription and activates ERK and Akt. Thus, the EGFR triggers distinct and mutually exclusive signaling networks, depending on the presence of ligand. Furthermore, noncanonical EGFRwt signaling may influence response to treatment in cancer. Also, there are reports of both synergistic and antagonistic interactions between ligand-dependent EGFRwt and EGFRvIII signaling. Here, we discuss ligand-independent EGFR signal transduction by oncogenic EGFR mutants and EGFRwt, and review the interplay between EGFRwt and EGFRvIII.

Clipping of very large or giant unruptured intracranial aneurysms in the anterior circulation: an outcome study.

OBJECT: Patients with very large or giant unruptured intracranial aneurysms present with ischemic stroke and progressive disability. The aneurysm rupture risk in these patients is extreme-up to 50% in 5 years. In this study the authors investigated the outcome of surgical treatment for these very large aneurysms in the anterior circulation. METHODS Clinical data on 62 patients who underwent surgery for unruptured aneurysms (20-60 mm) between 1998 and 2006 were reviewed. RESULTS: Complete aneurysm occlusion (100%) was achieved in 90% of cases, near complete occlusion (90-99%) in 5%. The surgical risk in patients younger than 50 years of age was 8% (Glasgow Outcome Scale score of 1 or 3 within 1 year after surgery). In older patients, the risk increased with advancing age. CONCLUSIONS: The treatment of very large or giant unruptured intracranial aneurysms is hazardous and complex and thus best performed only at major cerebrovascular centers with an experienced team of neurosurgeons, interventional neuroradiologists, neurologists, and neuroanesthesiologists. Surgery, with acceptable risks and excellent occlusion rates, is typically the treatment of choice in patients younger than 50 years of age. In older patients, the benefits of endovascular treatment versus surgery versus no treatment must be carefully weighed individually. Minimizing temporary occlusion and the consequent use of intraoperative angiography may help reduce surgical complications.