Carole A. Miller, MD: Matriarch of the Ohio State University's Department of Neurosurgery.

Carole A. Miller, M.D., was born (May 7, 1939) and raised in Kalamazoo, Michigan. She obtained her undergraduate and medical degrees at the Ohio State University. She went on to complete her neurosurgical training at the Ohio State University Medical Center. After her first faculty role at the University of Michigan (1971), she returned to the Ohio State University Medical Center (1975) where she spent nearly 4 decades. She thrived in the specialty, achieving in every facet of academic practice including scientific contributions, graduate medical education, clinical care, and leadership roles within her academic department, locally, and at the national level of organized neurosurgery. Dr. Miller passed away peacefully, on October 28, 2015, after a courageous battle with cancer. Based on her essential programmatic and specialty-related contributions, she is remembered as the 'founding mother' of neurosurgery at the Ohio State University.

Current Indications for Management Options in Pseudotumor Cerebri.

There are surgical options available for those patients with idiopathic intracranial hypertension (IIH) who have significant visual threat or visual deterioration despite best medical management or whose visual deterioration is rapid enough to warrant urgent intervention. Optic nerve sheath fenestrations, venous sinus stenting, and cerebrospinal fluid diversion via ventriculoperitoneal and lumboperitoneal shunting are useful adjuncts in the management of this condition. Significant resources are used in the care of patients with IIH. Further understanding of the pathophysiology of IIH will likely direct future treatment options to more targeted therapeutics including surgery for IIH in the future.

An institutional review of hospital resource utilization and patient radiation exposure in shunted idiopathic intracranial hypertension.

Patients with idiopathic intracranial hypertension (IIH) frequently utilize healthcare services and undergo radiological studies to assess refractory headache symptoms despite cerebrospinal fluid diversion. To delineate the clinical utility of different imaging modalities and to estimate cumulative patient radiation exposure in shunted patients with IIH, we retrospectively reviewed 100 randomly selected patients with IIH and a prior cerebrospinal fluid diversion procedure treated at our institution between July 2010 and August 2018. Patients had an average of 16.3 office (SD ± 13.8), 12.4 emergency department (± 21.0), and 4.6 inpatient (± 5.1) encounters over an average 4.8 years of follow-up. Patients underwent an average of 9.0 head CTs (± 8.1), 10.3 shunt series x-rays (± 11.2), and 4.3 MRIs (± 3.7). Approximated radiation exposure per patient was 21.4 mSv (± 18.7). Radiological studies performed for acute symptoms usually demonstrated no actionable findings (82.5% CTs, 97.5% shunt series x-rays, and 79.6% MRIs). Shunted IIH patients undergo numerous radiological studies and are subject to considerable levels of radiation, yet imaging shows actionable findings in less than 10% percent of radiographic studies. IIH patients may benefit from radiation-reducing protocols and the use of alternative imaging to assess symptoms.

Linear accelerator-based radiosurgery is associated with lower incidence of radionecrosis compared with gamma knife for treatment of multiple brain metastases.

BACKGROUND: Gamma knife (GK) and linear accelerator (LINAC)-based stereotactic radiosurgery (SRS) both offer excellent local control in the management of multiple brain metastases. The efficacy and toxicity of LINAC and GK SRS have not been directly compared in the modern era. We studied outcomes in patients treated with LINAC SRS and GK at two separate institutions. METHODS: We identified patients treated with either LINAC or GK who were treated to ≥2 lesions and had available follow up. LINAC patients were treated using single-isocenter multitarget technique. We used Cox regression, Fine and Gray competing risks regression, and nearest neighbor propensity score matching to account for confounders and imbalance between cohorts. Kaplan-Meier curves were used to estimate overall survival and rates of radionecrosis. RESULTS: We identified 391 patients who were treated in 537 courses to a total 2699 lesions (LINAC: 1014, GK: 1685). After propensity score matching, GK was associated with similar overall survival (HR = 0.86; 95% CI 0.59-1.24; p = 0.41) and higher rate of radionecrosis (HR = 3.83; 95% CI 1.66-8.84; p = 0.002) compared to LINAC. In a secondary propensity score matched analysis comparing radionecrosis in single-fraction LINAC and GK, GK remained associated with higher incidence of radionecrosis (HR = 4.42; 95% CI 1.28-15.29; p = 0.019). CONCLUSIONS: In this multi-institutional study, we found similar overall survival with lower incidence of radionecrosis in patients treated with LINAC compared to GK SRS. These findings are hypothesis generating and should be validated in an independent cohort.

Single-Isocenter Multitarget Stereotactic Radiosurgery Is Safe and Effective in the Treatment of Multiple Brain Metastases.

PURPOSE: Multiple studies have reported favorable outcomes for stereotactic radiosurgery (SRS) in the treatment of limited brain metastases. An obstacle of SRS in the management of numerous metastases is the longer treatment time using traditional radiosurgery. Single-isocenter multitarget (SIMT) SRS is a novel technique that permits rapid therapy delivery to multiple metastases. There is a lack of clinical evidence regarding its efficacy and safety. We report the outcomes of patients treated with this technique. METHODS AND MATERIALS: We reviewed the records of patients with intact or resected brain metastases treated with SRS in 1 to 5 fractions using SIMT technique at our institution, with at least 1 available follow-up brain magnetic resonance imaging. Survival, disease control, and toxicity were evaluated using Cox regression, logistic regression, and Kaplan-Meier analysis. RESULTS: We identified 173 patients with 1014 brain metastases. Median follow up was 12.7 months. Median beam-on time was 4.1 minutes. The median dose to the brain was 219.4 cGy. Median overall survival and freedom from intracranial progression were 13.2 and 6.3 months, respectively. Overall survival did not differ between patients treated with greater than or less than 4 lesions (hazard ratio, 1.03; 95% confidence interval 0.66-1.61; P = .91). Actuarial 1- and 2-year local control were 99.0% and 95.1%, respectively. Rates of grade 2 and grade 3 or higher radionecrosis were 1.4% and 0.9%, respectively. CONCLUSIONS: SIMT radiosurgery delivered in 1 to 5 fractions offers excellent local control and acceptable toxicity in the treatment of multiple intact and postoperative brain metastases. This technique should be evaluated prospectively.

Analysis of lesion localisation at colonoscopy: outcomes from a multi-centre U.K. study.

BACKGROUND: Colonoscopy is currently the gold standard for detection of colorectal lesions, but may be limited in anatomically localising lesions. This audit aimed to determine the accuracy of colonoscopy lesion localisation, any subsequent changes in surgical management and any potentially influencing factors. METHODS: Patients undergoing colonoscopy prior to elective curative surgery for colorectal lesion/s were included from 8 registered U.K. sites (2012-2014). Three sets of data were recorded: patient factors (age, sex, BMI, screener vs. symptomatic, previous abdominal surgery); colonoscopy factors (caecal intubation, scope guide used, colonoscopist accreditation) and imaging modality. Lesion localisation was standardised with intra-operative location taken as the gold standard. Changes to surgical management were recorded. RESULTS: 364 cases were included; majority of lesions were colonic, solitary, malignant and in symptomatic referrals. 82% patients had their lesion/s correctly located at colonoscopy. Pre-operative CT visualised lesion/s in only 73% of cases with a reduction in screening patients (64 vs. 77%; p = 0.008). 5.2% incorrectly located cases at colonoscopy underwent altered surgical management, including conversion to open. Univariate analysis found colonoscopy accreditation, scope guide use, incomplete colonoscopy and previous abdominal surgery significantly influenced lesion localisation. On multi-variate analysis, caecal intubation and scope guide use remained significant (HR 0.35, 0.20-0.60 95% CI and 0.47; 0.25-0.88, respectively). CONCLUSION: Lesion localisation at colonoscopy is incorrect in 18% of cases leading to potentially significant surgical management alterations. As part of accreditation, colonoscopists need lesion localisation training and awareness of when inaccuracies can occur.

Phase II multicenter study of gene-mediated cytotoxic immunotherapy as adjuvant to surgical resection for newly diagnosed malignant glioma.

BACKGROUND: Despite aggressive standard of care (SOC) treatment, survival of malignant gliomas remains very poor. This Phase II, prospective, matched controlled, multicenter trial was conducted to assess the safety and efficacy of aglatimagene besadenovec (AdV-tk) plus valacyclovir (gene-mediated cytotoxic immunotherapy [GMCI]) in combination with SOC for newly diagnosed malignant glioma patients. METHODS: Treatment cohort patients received SOC + GMCI and were enrolled at 4 institutions from 2006 to 2010. The preplanned, matched-control cohort included all concurrent patients meeting protocol criteria and SOC at a fifth institution. AdV-tk was administered at surgery followed by SOC radiation and temozolomide. Subset analyses were preplanned, based on prognostic factors: pathological diagnosis (glioblastoma vs others) and extent of resection. RESULTS: Forty-eight patients completed SOC + GMCI, and 134 met control cohort criteria. Median overall survival (OS) was 17.1 months for GMCI + SOC versus 13.5 months for SOC alone (P = .0417). Survival at 1, 2, and 3 years was 67%, 35%, and 19% versus 57%, 22%, and 8%, respectively. The greatest benefit was observed in gross total resection patients: median OS of 25 versus 16.9 months (P = .0492); 1, 2, and 3-year survival of 90%, 53%, and 32% versus 64%, 28% and 6%, respectively. There were no dose-limiting toxicities; fever, fatigue, and headache were the most common GMCI-related symptoms. CONCLUSIONS: GMCI can be safely combined with SOC in newly diagnosed malignant gliomas. Survival outcomes were most notably improved in patients with minimal residual disease after gross total resection. These data should help guide future immunotherapy studies and strongly support further evaluation of GMCI for malignant gliomas. CLINICAL TRIAL REGISTRY: ClinicalTrials.gov NCT00589875.

A survey of morbidity and mortality review meetings in the general surgical units of the West of Scotland.

BACKGROUND AND AIMS: There is little consensus as to the conduct of surgical morbidity and mortality review meetings. The aim of this survey was to determine how surgical morbidity and mortality meetings in the surgical units in the West of Scotland are carried out and to explore possible areas for improvement. METHODS AND RESULTS: Forty six surgical trainees distributed between the 15 general surgery units of the West of Scotland were asked to provide details of their surgical morbidity and mortality meetings for the training year 2012-2013. Twenty-five of 46 (54%) specialty trainees responded with all units being represented. All had designated time for surgical morbidity and mortality review. Meeting frequency varied as follows: weekly (3 units), fortnightly (1 unit), monthly (10 units), three monthly (1 unit). Fewer than half the units (6) included Foundation Trainees, and only one meeting was attended by nursing staff. Five units had clear criteria for morbidity, but only three included morbidity collected from outpatient follow-up. A standardised proforma was used to present the cases in only 2 units. CONCLUSIONS: All 15 surgical units in the West of Scotland have a regular surgical morbidity and mortality meeting but significant variations were observed as to frequency and participating personnel. A more robust system for reporting morbidities should be considered.

Unsanctifying the sanctuary: challenges and opportunities with brain metastases.

While the use of targeted therapies, particularly radiosurgery, has broadened therapeutic options for CNS metastases, patients respond minimally and prognosis remains poor. The inability of many systemic chemotherapeutic agents to penetrate the blood-brain barrier (BBB) has limited their use and allowed brain metastases to become a burgeoning clinical challenge. Adequate preclinical models that appropriately mimic the metastatic process, the BBB, and blood-tumor barriers (BTB) are needed to better evaluate therapies that have the ability to enhance delivery through or penetrate into these barriers and to understand the mechanisms of resistance to therapy. The heterogeneity among and within different solid tumors and subtypes of solid tumors further adds to the difficulties in determining the most appropriate treatment approaches and methods of laboratory and clinical studies. This review article discusses therapies focused on prevention and treatment of CNS metastases, particularly regarding the BBB, and the challenges and opportunities these therapies present.

A multiscale model for the study of cardiac biomechanics in single-ventricle surgeries: a clinical case.

Complex congenital heart disease characterized by the underdevelopment of one ventricular chamber (single ventricle (SV) circulation) is normally treated with a three-stage surgical repair. This study aims at developing a multiscale computational framework able to couple a patient-specific three-dimensional finite-element model of the SV to a patient-specific lumped parameter (LP) model of the whole circulation, in a closed-loop fashion. A sequential approach was carried out: (i) cardiocirculatory parameters were estimated by using a fully LP model; (ii) ventricular material parameters and unloaded geometry were identified by means of the stand-alone, three-dimensional model of the SV; and (iii) the three-dimensional model of SV was coupled to the LP model of the circulation, thus closing the loop and creating a multiscale model. Once the patient-specific multiscale model was set using pre-operative clinical data, the virtual surgery was performed, and the post-operative conditions were simulated. This approach allows the analysis of local information on ventricular function as well as global parameters of the cardiovascular system. This methodology is generally applicable to patients suffering from SV disease for surgical planning at different stages of treatment. As an example, a clinical case from stage 1 to stage 2 is considered here.

"Tumoral pseudoblush" identified within gliomas at high-spatial-resolution ultrahigh-field-strength gradient-echo MR imaging corresponds to microvascularity at stereotactic biopsy.

PURPOSE: To use directed biopsy sampling to determine whether microvascular assessment within gliomas, by means of ultrahigh-field-strength high-spatial-resolution gradient-echo (GRE) magnetic resonance (MR) imaging at 8 T, correlates with histopathologic assessment of microvascularity. MATERIALS AND METHODS: The study was institutional review board approved and HIPAA compliant. Informed consent was obtained. Thirty-five subjects with gliomas underwent 8-T and 80-cm MR imaging by using a GRE sequence (repetition time, 600-750 msec; echo time, 10 msec; in-plane resolution, 196 mm). Haphazardly arranged serpentine low-signal-intensity structures, often associated with areas of low signal intensity within the tumor bed ("tumoral pseudoblush") at MR imaging, were presumed to be related to tumoral microvascularity. Microvessel density (MVD) and microvessel size (MVS) ranked with a semiquantitative three-tier scale (high, medium, and low) relative to cortical penetrating veins were assessed from regions of interest identified at MR imaging and were compared with a similar assessment of stereotactic biopsy specimens by using Kendall τb. Tumor grade (high vs low) was compared with ultrahigh-field-strength high-resolution GRE MR analysis by using Pearson χ2. Discrepancies between 8-T and histopathologic assessment were identified and analyzed. RESULTS: Ultrahigh-field-strength high-resolution GRE MR imaging and histopathologic assessment concurred for MVS (P<.0001) and MVD (P<.0001). World Health Organization classification tumor grade was associated with number (P<.0005) and size (P<.0005) of foci of microvascularity within the tumor bed at 8-T MR imaging. Radiation-induced microvessel hyalinosis mimicked tumor microvascularity at 8-T MR imaging. Potential confounders could result from radiofrequency inhomogeneity and displaced normal microvasculature. CONCLUSION: Microvascularity identified as a tumoral pseudoblush at ultrahigh-field-strength high-resolution GRE MR imaging without contrast material shows promise as a marker for increased tumoral microvascularity.

Extracorporeal membrane oxygenation for complex multiorgan system trauma.

With growing experience, the indications for salvage extracorporeal membrane oxygenation continue to expand. We describe a successful application of extracorporeal support in a polytrauma patient presenting with profound hypothermia, respiratory failure, and whom was later found to have an intracranial hemorrhage. We advocate the role of salvage therapy even in patients with complex pathophysiology despite perceived relative or absolute contraindications to extracorporeal support.

Phase IB study of gene-mediated cytotoxic immunotherapy adjuvant to up-front surgery and intensive timing radiation for malignant glioma.

PURPOSE: Despite aggressive therapies, median survival for malignant gliomas is less than 15 months. Patients with unmethylated O(6)-methylguanine-DNA methyltransferase (MGMT) fare worse, presumably because of temozolomide resistance. AdV-tk, an adenoviral vector containing the herpes simplex virus thymidine kinase gene, plus prodrug synergizes with surgery and chemoradiotherapy, kills tumor cells, has not shown MGMT dependency, and elicits an antitumor vaccine effect. PATIENTS AND METHODS: Patients with newly diagnosed malignant glioma received AdV-tk at 3 × 10(10), 1 × 10(11), or 3 × 10(11) vector particles (vp) via tumor bed injection at time of surgery followed by 14 days of valacyclovir. Radiation was initiated within 9 days after AdV-tk injection to overlap with AdV-tk activity. Temozolomide was administered after completing valacyclovir treatment. RESULTS: Accrual began December 2005 and was completed in 13 months. Thirteen patients were enrolled and 12 completed therapy, three at dose levels 1 and 2 and six at dose level 3. There were no dose-limiting or significant added toxicities. One patient withdrew before completing prodrug because of an unrelated surgical complication. Survival at 2 years was 33% and at 3 years was 25%. Patient-reported quality of life assessed with the Functional Assessment of Cancer Therapy-Brain (FACT-Br) was stable or improved after treatment. A significant CD3(+) T-cell infiltrate was found in four of four tumors analyzed after treatment. Three patients with MGMT unmethylated glioblastoma multiforme survived 6.5, 8.7, and 46.4 months. CONCLUSION: AdV-tk plus valacyclovir can be safely delivered with surgery and accelerated radiation in newly diagnosed malignant gliomas. Temozolomide did not prevent immune responses. Although not powered for efficacy, the survival and MGMT independence trends are encouraging. A phase II trial is ongoing.

Endothelial nitric oxide synthase is a key mediator of interleukin-2-induced hypotension and vascular leak syndrome.

Despite increasing use of "targeted therapy," interleukin-2 (IL-2) is unique, because this cytokine can induce long-term remissions in 5% to 7% of patients with metastatic melanoma and renal cancer. Clinical use of IL-2 is limited by severe toxicities, such as hypotension and vascular leak syndrome (VLS). Nitric oxide seems to be involved in the pathogenesis of these toxicities. On the basis of previous studies, we hypothesized that the endothelial nitric oxide synthase (eNOS) is the major source of nitric oxide. Mice with a knockout of the eNOS isoenzyme were treated with IL-2 (800,000 IU twice daily for 5 d). Blood pressure and vascular leak were measured. Inhibitors of superoxide, nitric oxide, and soluble guanylate cyclase were used to probe the mechanism. These experiments showed that IL-2 treatment increased eNOS messenger ribonucleic acid expression and nitric oxide metabolite excretion in eNOS knockout mice. Unlike normal and inducible nitric oxide synthase knockout mice, eNOS knockout mice proved resistant to IL-2-induced hypotension and vascular leak. Although hypotension seems to be mediated by superoxide or peroxynitrite, vascular leak seemed to be mediated by nitric oxide. Inhibition of guanylate cyclase and cyclic guanylate monophosphate formation during IL-2 treatment using methylene blue (MB)-inhibited vascular leak. MB treatment did not interfere with IL-2-induced antitumor mechanisms. Our experiments established that eNOS is a key mediator of IL-2-induced VLS and hypotension. A clinical trial of MB infusion during IL-2 therapy is currently being planned.

Stereotactic radiosurgery alone for patients with 1-4 radioresistant brain metastases.

Brain metastases from radioresistant histologies are perceived to be less responsive to WBRT compared to other histologies, and stereotactic radiosurgery (SRS) may provide better local control. The aim of this study was to examine the outcomes of patients with 1-4 brain metastasis from radioresistant histologies (renal cell carcinoma and melanoma) treated with SRS alone. Thirty-eight patients with 1-4 radioresistant brain metastases (66 lesions) were treated with SRS alone. The median age was 55 years. Fourteen and 24 patients had renal cell carcinoma (RCC) and melanoma brain metastases, respectively. Distribution of number of lesions was as follows: one lesion, 22 patients; 2 lesions, 8 patients; 3 lesions, 5 patients; and 4 lesions, 3 patients. Distribution of RTOG recursive partitioning analysis (RPA) classes was as follows: II, 37 patients and III, 1 patient. The median marginal dose was 20 Gy. The median follow-up was 6.1 months. The 3-, 6-, 9-, 12-, and 18-month local control (LC) rates were 87.9, 81.4, 67.9, 67.9, and 60.3%, respectively. The corresponding free-from-distant-brain failure (FFDBF) rates were 71.3, 58.1, 49.8, 40.2, and 27.6%. The corresponding progression-free survival (PFS) rates were 55.3, 41.9, 33, 23.3, and 13.3%. RCC histology was associated with better LC (P = 0.0055). Although SRS alone could yield reasonable LC in patients with 1-4 radioresistant brain metastases, the risk of distant brain failure was substantial. The approach of routine omission of WBRT outside of a trial setting should be used judiciously.

Intracerebroventricular morphine for refractory cancer pain: transitioning to the home setting.

Refractory cancer pain may be effectively controlled by titrating intracerebroventricular (ICV) preservative-free opioid. In this case report, a continuous infusion of ICV morphine permitted our patient with lung cancer and painful spinal metastases to be discharged to home hospice with family. The approach exploits the high potency of morphine injected into cerebrospinal fluid (CSF). Sterile, injectable, preservative-free morphine is directly infused into CSF through a subcutaneous Ommaya reservoir placed under the scalp by a neurosurgeon, with an attached catheter passed through a burr hole in the skull with its tip in a cerebral ventricle. Although investigators have described home care of patients receiving intraspinal analgesics, no report describes the process of transitioning the patient receiving continuous ICV morphine infusion to the home setting.

Stereotactic radiosurgery with or without whole brain radiotherapy for patients with a single radioresistant brain metastasis.

PURPOSE: To examine the outcomes of patients with a single brain metastasis from radioresistant histologies (renal cell carcinoma and melanoma) treated with stereotactic radiosurgery (SRS) with or without whole brain radiotherapy (WBRT). METHODS AND MATERIALS: We reviewed the medical records of 27 patients treated at our institution between 2000 and 2007 with a single radioresistant brain metastasis. Patients were treated with Gamma Knife based SRS. Tumor histologies included renal cell carcinoma and melanoma. RESULTS: Patients were treated to a median marginal dose was 20 Gy (range, 15-22 Gy). At follow-up intervals ranging from 1.8 to 23.2 months, the radiographic responses were as follows: progression in 7 patients; stable in 5 patients; and shrinkage in 15 patients. Fifteen patients (56%) developed distant brain failure. Seven of the 27 patients were alive at last follow-up. The 3-, 6-, 9-, 12-, and 18-months after SRS local control rates were 82.8%, 77.9%, 69.3%, 69.3%, and 55.4%, respectively. None of the 5 patients who received WBRT developed distant brain failure although the follow-up intervals were short (range, 3.5-13.7 months; median, 5.1 months). WBRT did not appear to affect local control, progression free survival, and overall survival (P = 0.32, 0.87, 0.69). One patient developed worsening of symptoms attributable to SRS. CONCLUSIONS: Gamma Knife SRS is a safe and feasible strategy for treatment of patients with a single radioresistant brain metastasis. Radiosurgery alone is a reasonable treatment option, but may carry a greater likelihood of distant brain recurrence.

Stereotactic radiosurgery and stereotactic radiotherapy in the treatment of skull base meningiomas.

Meningiomas are the most common nonglial brain tumors. They tend to be slow growing and benign and can reach substantial sizes before becoming symptomatic. Complete surgical resection of intracranial meningiomas remains the treatment of choice. Location of a meningioma within the cranial vault may make complete surgical resection unlikely; tumors arising from the dura of the skull base are particularly challenging. Advances in radiation therapy, including stereotactic techniques, can expand the options for treatment available in these situations. They may be used as adjuncts to surgery or as alternative modalities in the treatment of these complex tumors.