Faculty Bibliography

INTRODUCTION: It is known that physicians sometimes recommend treatment that, in a similar clinical scenario, they might not choose for themselves. We sought to understand this dynamic across cerebrovascular practice and examine how neurosurgeons value the procedures they offer. METHODS: We conducted an online survey sent to a large cohort of neurosurgeons in May 2013. Respondents were randomised to answer either as the surgeon or as the patient. The questions involved patients presenting with 1) an epidural hematoma (control), 2) un-ruptured anterior communicating artery aneurysm, 3) incidentally found right temporal AVM, 4) spontaneous intracranial and intraventricular haemorrhage in deep structure. Data on practice parameters and experience levels was also collected. RESULTS: We obtained 534 survey responses, 279 responding as the "neurosurgeon", and 255 as the "patient," with a response rate of 19.7%. Demographics amongst the two groups of survey takers was similar. There was no difference in the management of an epidural hematoma, as expected. For the unruptured aneurysm, the rates of opting for treatment was similar amongst respondees. However within the treatment group there was a trend for survey takers to more often chose coiling for themselves and clipping for patients (p = 0.056). Surgeons, however, with a greater than 30% open-cerebrovascular practice had less of a tendency to do so. For arteriovenous malformation management, there was no statistical difference between choosing treatment or conservative management. However, amongst the respondees who chose treatment, more respondees chose resection/embolization for their patient but radiosurgery for self (p = 0.001). In a case of a large spontaneous intracranial and intraventricular haemorrhage neurosurgeons were more likely to place a ventricular drain in a patient than himself or herself. Neurosurgeons in practice more than 10 years since residency were more likely to recommend against interventions for aneurysms, AVMs or intracranial haemorrhage. CONCLUSIONS: In the majority of cases altering the role of the surgeon did not change the decision to pursue treatment or conservative treatment. In certain clinical scenarios, however, neurosurgeons choose treatment options for themselves that are different than what they would choose for their patients. For the management of an arteriovenous malformations, intracranial aneurysms, and hypertensive haemorrhage, responses favored less invasive interventions when the surgeon was the patient. These findings are likely a result of cognitive biases, previous training, experience, areas of expertise, and personal values. DISCLOSURES: O. Tanweer: None. T. Wilson: None. S. Kalhorn: None. J. Golfinos: None. P. Huang: None. D. Kondziolka: None.

Objective: To assess the complication and migration rates associated with fixation of cochlear implant receiver stimulators using a subperiosteal tight pocket without either suture fixation or bone recession. Study Design: Dual institution retrospective case review Methods: A retrospective case review was conducted at two tertiary referral centers. All patients who underwent cochlear implantation with device fixation using a subperiosteal tight pocket without suturing over the device or recessing of the receiver stimulator in bone were identified. There was a minimum follow-up period of six months. Outcome measures included intraoperative and postoperative complications, including evidence of device migration associated with interference with external device use or need for revision surgery. Other outcome measures included soft tissue flap complications. Results: Sixty-two patients were identified with a mean age of 39 years, (range 1.5-95 years). The average follow-up period was 32.6 months (range 6-120 months). Device manufacturers included Cochlear Corporation (n=44), MED-EL (n=12) and Advanced Bionics (n=6). There were no associated intraoperative complications related to subperiosteal pocket fixation of the receiver stimulator, and no cases of migration were identified. Conclusion: Fixation of the cochlear implant receiver stimulator using a subperiosteal tight pocket without either suture fixation or bone recession has been demonstrated to be feasible across a range of patient demographics and cochlear implant devices. This method of fixation appears to allow for an efficient and minimally invasive approach without compromising patient safety or device performance.

OBJECTIVES/HYPOTHESIS/OBJECTIVE:Locoregional recurrence remains the primary failure pattern following salvage surgery for previously irradiated head and neck cancer; randomized trials have suggested a complimentary role for adjuvant chemotherapy and conventional reirradiation at the expense of significant increases in toxicity. We aimed to identify if stereotactic body radiotherapy (SBRT) ± cetuximab improves tumor control while reducing treatment-related toxicity following salvage surgery. STUDY DESIGN/METHODS:Retrospective review (2005-2011) of 28 patients with high-risk features (positive surgical margins or extranodal extension) following macroscopic complete (R0/R1) salvage surgery treated with adjuvant SBRT±cetuximab. METHODS:SBRT consisted of 40 to 44 Gy in five fractions over 1 to 2 weeks with concurrent cetuximab (n=7) administered at 400 mg/m2 day -7+250 mg/m2 days 0 and +8. Toxicity was physician recorded, and University of Washington Quality of Life Revised surveys were prospectively collected. RESULTS:All patients received prior radiotherapy (median, 70 Gy; range, 54-99 Gy) with a median reirradiation interval of 25 months (range, 6-156 months). At a median follow-up of 14 months (range, 2-69 months), the 1-year locoregional control, distant control, disease-free survival, and overall survival were 51%, 90%, 49%, and 64%, respectively. Rates of acute and late severe (≥grade 3) toxicity were low at 0% and 8%, respectively. At a median follow-up survey time of 6 months, 56% of patients reported improved/stable overall quality-of-life scores. CONCLUSIONS:Adjuvant SBRT±cetuximab following salvage surgery is well tolerated with acceptable oncologic outcomes and little toxicity. Future prospective trials should evaluate adjuvant SBRT±cetuximab versus a wait-and-see approach for recurrent head and neck cancers with high-risk features following salvage surgery. LEVEL OF EVIDENCE/METHODS:4.

Tumor cell survival consists of an intricate balance between cell growth and cell death pathways involving receptor tyrosine kinases [RTK; i.e., HER1-4, insulin-like growth factor-1 receptor (IGF-1R), etc.], MDM2, and the tumor suppressor proteins phosphatase and tensin homolog deleted on chromosome ten (PTEN) and p53. We recently demonstrated that shedded E-cadherin extracellular domain fragment (sEcad) is a valid oncogenic target that is significantly increased in human clinical skin squamous cell cancers (SCC) samples, UV-induced mouse tumors, and cells and promotes tumor cell proliferation, migration, and invasion by interacting and activating with the HER-phosphatidylinositol 3-kinase (PI3K)-Akt-mammalian target of rapamycin (mTOR) and mitogen-activated protein kinase (MAPK) axis. In resected human SCC tumors, we reported enhanced sEcad-HER1, sEcad-HER2, and sEcad-IGF-1R, but not FL-Ecad-RTK interactions. Here, we demonstrate that a sEcad antibody against the ectodomain of E-cadherin suppressed SCC growth and increased tumor differentiation in orthotopic cutaneous SCC xenografts by inhibiting proliferation and inducing apoptosis. A similar anti-sEcad antibody-induced inhibition of proliferation and induction of cell death was evident in PAM212 cells in vitro. Mechanistically, anti-sEcad administration upregulated an array of cell death pathways (i.e., Bad, active caspase-3, and cleaved PARP) and inhibited inhibitors of apoptosis (IAP; survivin, livin, etc.), RTKs (HER1, HER2, p95HER2, and IGF-1R), MAPK and PI3K/mTOR prosurvival signaling. Interestingly, in anti-sEcad mAb-treated tumors and PAM212 cells, this effect was associated with a profound increase in membrane, cytosolic, and nuclear levels of PTEN; enhanced cytosolic p53; and a decrease in MDM2 levels. Overall, our studies suggest that an antibody-based therapy against sEcad may be a novel therapeutic platform for cutaneous SCCs by hampering key proto-oncogenes (RTKs, IAPs, and MDM2) and activating potent tumor suppressor proteins (PTEN and p53) intricately linked to tumor growth and survival.

IMPORTANCE/OBJECTIVE:Laboratory and clinical studies have shown that vacuum-assisted closure (VAC) therapy increases wound blood flow and granulation tissue formation and decreases accumulation of fluid and bacteria. Many publications outline the use of VAC dressings in the treatment of sternal, sacral, upper and lower extremity, perineal, and abdominal wounds, but few describe its use in the head and neck region. No report to date has addressed the use of VAC therapy in helping to preserve facial nerve integrity. OBSERVATIONS/METHODS:We present a case of a 64-year-old woman who underwent tissue debridement for necrotizing fasciitis of the left face, neck, and upper chest. She subsequently had exposed facial nerve that was covered with a VAC dressing and demonstrated complete granulation by postoperative day 7 with preservation of function. CONCLUSIONS AND RELEVANCE/CONCLUSIONS:This case highlights the effectiveness of VAC in eliminating infectious material and promoting granulation tissue formation. This is the first time that VAC therapy has been shown to maintain neural function when placed directly on functioning cranial nerves.

OBJECTIVES/HYPOTHESIS/OBJECTIVE:To determine posttreatment quality of life (QOL) in head and neck cancer patients, stratifying by human papillomavirus (HPV)/p16 status and primary treatment modality. STUDY DESIGN/METHODS:Retrospective study. METHODS:One hundred and seventy-seven patients (N=177) with head and neck squamous cell carcinoma and known HPV/p16 status were included. All patients completed at least one baseline or posttreatment University of Washington QOL survey. QOL scores were averaged and compared across patients, stratifying by HPV/p16 status and primary treatment modality (surgical vs. nonsurgical). In the analysis, p16 was used as a surrogate marker for HPV. RESULTS:Of the 177 patients, 80 (45.2%) were p16-positive and 49.7% of subsites were oropharyngeal. Nearly 60% (105/177) of patients underwent primary surgery, 26.7% (28/105) of patients with transoral robotic or laser techniques. The remainder 40.7% of patients underwent primary radiation and/or chemotherapy. Overall, QOL scores were better for p16-positive patients compared to p16-negative patients at baseline (P=0.008), at 6 months posttreatment (P=0.034), and at greater than 1 year posttreatment (P=0.013). P16-positive patients had better QOL scores in speech (P=0.0009), chewing (P=0.0004), and swallowing (P=0.021) after 1 year posttreatment compared to p16-negative patients. Primary treatment modality did not affect overall QOL or any of the 12 QOL categories in p16-positive patients at any time point. At over 1 year posttreatment, QOL was at or above baseline in both p16-positive treatment groups. CONCLUSION/CONCLUSIONS:The p16-positive patients had better baseline and posttreatment overall QOL compared to p16-negative patients. The overall and category specific QOL scores for p16-positive patients were not affected by primary treatment modality. LEVEL OF EVIDENCE/METHODS:4.

A novel method of common-path imaging interferometry, the White Light Spatial-Phase-Shift (WLSPS) for object surface measurements, is discussed here. Compared to standard White Light Interferometry (WLI), which uses a reference mirror, the interferometry of WLSPS is obtained by creating manipulations to the light wavefront reflected from an object's surface. Using this approach, surface measurements can be obtained from any real object image, and do not need to be taken directly from the object itself. This creates the ability for a surface measurement tool to be attached to any optical system that generates a real image of an object. Further, as this method does not require a reference beam, the surface measurement system contains inherent vibration cancelation.

BACKGROUND:The determination of in situ protein levels of ERCC1 with the 8F1 monoclonal antibody is prognostic of survival in patients with non-small cell lung cancer (NSCLC). The authors previously demonstrated that 8F1 recognizes a second nuclear antigen. This antigen was identified and its value as a biomarker of clinical outcomes analyzed. METHODS:The second antigen was identified by mass spectrometry. Protein identity and antibody specificity were confirmed through knockdown and overexpression experiments. Immunohistochemistry of 187 early-stage NSCLC samples and 60 head and neck squamous cell carcinomas (HNSCCs) was used to examine the influence of the second antigen on 8F1 immunoreactivity and its association with patient outcomes. RESULTS:Choline phosphate cytidylyltransferase-α (CCTα, also known as phosphate cytidylyltransferase 1 choline alpha [PCYT1A], a phospholipid synthesis enzyme regulated by RAS) is the second antigen recognized by 8F1. In NSCLC samples, CCTα contributed (rho, 0.38) to 8F1 immunoreactivity. In samples of squamous cell carcinomas of the lung, CCTα was found to be the dominant determinant of 8F1 immunoreactivity, whereas its contribution in other subtypes of lung cancer was negligible. High expression of CCTα, but not ERCC1, was found to be prognostic of longer disease-free survival (log-rank P = .002) and overall survival (log-rank P = .056). Similarly, in patients with HNSCC, CCTα contributed strongly to 8F1 immunoreactivity (rho, 0.74), and high CCTα expression was found to be prognostic of survival (log-rank P = .022 for disease-free survival and P = .027 for overall survival). CONCLUSIONS:CCTα is the second antigen detected by 8F1. High CCTα expression appears to be prognostic of survival in patients with NSCLC who are treated by surgery alone and patients with HNSCC. CCTα is a promising biomarker of patient survival and deserves further study.

PURPOSE/OBJECTIVE:Idiotypes (Ids), the unique portions of tumor immunoglobulins, can serve as targets for passive and active immunotherapies for lymphoma. We performed a multicenter, randomized trial comparing a specific vaccine (MyVax), comprising Id chemically coupled to keyhole limpet hemocyanin (KLH) plus granulocyte macrophage colony-stimulating factor (GM-CSF) to a control immunotherapy with KLH plus GM-CSF. PATIENTS AND METHODS/METHODS:Patients with previously untreated advanced-stage follicular lymphoma (FL) received eight cycles of chemotherapy with cyclophosphamide, vincristine, and prednisone. Those achieving sustained partial or complete remission (n=287 [44%]) were randomly assigned at a ratio of 2:1 to receive one injection per month for 7 months of MyVax or control immunotherapy. Anti-Id antibody responses (humoral immune responses [IRs]) were measured before each immunization. The primary end point was progression-free survival (PFS). Secondary end points included IR and time to subsequent antilymphoma therapy. RESULTS:At a median follow-up of 58 months, no significant difference was observed in either PFS or time to next therapy between the two arms. In the MyVax group (n=195), anti-Id IRs were observed in 41% of patients, with a median PFS of 40 months, significantly exceeding the median PFS observed in patients without such Id-induced IRs and in those receiving control immunotherapy. CONCLUSION/CONCLUSIONS:This trial failed to demonstrate clinical benefit of specific immunotherapy. The subset of vaccinated patients mounting specific anti-Id responses had superior outcomes. Whether this reflects a therapeutic benefit or is a marker for more favorable underlying prognosis requires further study.