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Lorenzo Rinaldo, Desmond Brown, Giuseppe Lanzino, and Ian F. Parney

OBJECTIVE

The clinical course of high-grade central nervous system gliomas is occasionally complicated by hydrocephalus. The risks of shunt placement and clinical outcome following CSF diversion in this population are not well defined.

METHODS

The authors retrospectively reviewed the outcomes of patients with pathologically confirmed WHO grade III or IV gliomas with shunt-treated hydrocephalus at their institution. Outcomes of patients in this cohort were compared with those of patients who underwent shunt treatment for normal pressure hydrocephalus (NPH). Hospital-reported outcomes in a national database for malignant primary brain tumor patients undergoing a ventricular shunt procedure were also reviewed.

RESULTS

Forty-one patients undergoing CSF shunting between 2001 and 2016 at the authors’ institution were identified. Noncommunicating and communicating hydrocephalus occurred at similar rates (51.2% vs 48.8%). Symptomatic improvement after shunting was observed in 75.0% of patients. A major complication occurred in 17.1% of cases, with 2 patients suffering an intracranial hemorrhage. Prior administration of bevacizumab was significantly associated with the incidence of hemorrhage (p = 0.026). Three patients (7.3%) died during admission, and 8 (19.5%) died within 30 days of shunt placement. The presence of ependymal or leptomeningeal enhancement was more common in patients who died within 30 days (75.0% vs 11.1%, p = 0.001). Six patients (18.1%) required readmission to the hospital within 30 days of discharge. Revision surgery was necessary in 7 patients (17.1%). The median time from shunt placement to death was 150.5 days. In comparison with patients with NPH, shunt-treated high-grade glioma patients had increased in-hospital (7.3% vs 0.5%, p = 0.008) and 30-day (19.5% vs 0.8%, p < 0.001) mortality but no difference in the incidence of revision surgery (17.1% vs 17.5%, p = 0.947). Similarly, in the national Vizient Clinical Database Resource Manager, shunt-treated patients with malignant primary brain tumors had an increased length of stay (6.9 vs 3.5 days, p < 0.001), direct cost of admission ($15,755.80 vs $9871.50, p < 0.001), and 30-day readmission rates (20.6% vs 2.4%, p < 0.001) compared with patients without brain tumors who received a shunt for NPH.

CONCLUSIONS

Shunting can be an effective treatment for the symptoms of hydrocephalus in patients with high-grade gliomas. However, the authors’ results suggest that this procedure carries a significant risk of complications in this patient population.

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Ian F. Parney and David E. Steinke

U The authors present a case of heparin-induced thrombocytopenia and thrombosis (HITT) that occurred after aneurysmal subarachnoid hemorrhage (SAH), and they review the relevant literature. An immune-mediated syndrome, HITT is characterized by moderate thrombocytopenia and paradoxical vascular thromboses. Although it has been estimated in prospective studies that HITT occurs in between 1 and 3% of patients receiving heparin, it is underrecognized in the neurosurgical literature. In the present case, a 49-year-old woman underwent clipping of a right posterior communicating artery aneurysm after suffering a Hunt and Hess Grade III SAH. She had an uncomplicated postoperative course with good clip positioning and no vasospasm observed on a cerebral angiogram obtained on Day 7.

On Day 23, the patient developed a right hemiparesis and experienced a grand mal seizure. A head computerized tomography scan revealed a hemorrhagic infarct in the left middle cerebral artery distribution. Repeated cerebral angiograms did not show vasospasm. She was thrombocytopenic (platelet count as low as 46 × 109/L on Day 28 compared with 213 × 109/L on Day 1) and had been receiving heparin flushes to maintain intravenous catheter patency. An assay for HITT-associated antibodies was positive. The heparin flushes were discontinued and the platelet count recovered (121 × 109/L). She improved neurologically, but was left with a significant right hemiparesis at discharge. This patient had assay-proven heparin-induced thrombocytopenia despite minimal exposure to heparin. Because there was no evidence of vasospasm or other factors to account for her delayed hemorrhagic infarction, an HITT-related disorder seemed most likely. Despite a large body of literature describing HITT in nonneurosurgical patients, only three previous neurosurgical cases have been published. This case report may serve to heighten awareness of this disorder.

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Ian F. Parney, James S. Waldron, and Andrew T. Parsa

Object

To date, glioma immunotherapy has been focused mostly on stimulating antitumor peripheral lymphocyte responses; however, some data suggest that microglia and/or macrophages (not lymphocytes) are the predominant inflammatory cells infiltrating gliomas. To study this hypothesis further, the authors analyzed inflammatory cell infiltrates in fresh human malignant glioma specimens and primary cultures.

Methods

Single-cell suspensions from fresh operative malignant glioma specimens, obtained by stereotactic localization, were analyzed for CD11b and CD45 by using flow cytometry. A comparison was made with peripheral blood mononuclear cells. In a subset of patients, a more detailed flow cytometry analysis of Class I and II major histocompatibility complex, B7-1, B7-2, CD11c, and CD14 expression was performed. Macrophage-like cells in primary glioma cultures were similarly assessed.

Results

Operative samples were obtained from 9 newly diagnosed malignant gliomas. The mean percent of CD45+/CD11b cells (lymphocytes) was 2.48% (range 0.65–5.50%); CD45dim/CD11b+ cells (microglia), 1.65% (range 0.37–3.92%); and CD45bright/CD11b+ (monocytes/macrophages), 6.25% (range 1.56–15.3%). More detailed fluorescence-activated cell sorting suggested that macrophage-like cells expressed Class I and II major histocompatibility complex, B7-2, and CD11c but not CD14 or B7-1. Primary human glioma cultures contained significant numbers of macrophage-like (CD45bright/CD11b+) cells, but these cells were lost with successive passages. These cells maintained the immunomarker profiles of macrophage-like cells from fresh specimens only if they were cultured in serum-free media.

Conclusions

The CD45+/CD11b+ cells are the predominant inflammatory cell infiltrating human gliomas. Of this type, the CD45bright/CD11b+ cells, a phenotype compatible with circulating macrophages in rodent models, and not microglia, are the most common. Their immunomarker profile is compatible with an immature antigen-presenting cell. They are present in primary glioma cultures but are lost in successive passages. Their role is enigmatic, and they may prove an important target for future glioma immunotherapy studies.

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Grant W. Mallory, Shanna Fang, Caterina Giannini, Jamie J. Van Gompel, and Ian F. Parney

Object

Carcinoid tumors are rare and have generally been regarded as indolent neoplasms. Systemic disease is often incurable; however, patients may live years with this disease. Furthermore, metastatic brain lesions are extremely uncommon. As such, few series have examined outcomes and prognostic factors in those with brain involvement.

Methods

The authors performed a retrospective review of patients who underwent primary treatment at Mayo Clinic in Rochester, Minnesota, for metastatic carcinoid tumors to the brain between 1986 and 2011. Progression-free survival (PFS) and overall survival (OS) were analyzed using Kaplan-Meier statistics. Cox proportional hazards were used to determine predictors of survival.

Results

Fifteen patients underwent primary treatment for metastatic carcinoid tumors to the brain between 1986 and 2011. Their mean age was 58 ± 12 years. Eighty percent (n = 12) of patients underwent surgery, whereas 2 received stereotactic radiosurgery and 1 had whole-brain radiation therapy (WBRT) as the primary treatment. The median follow-up duration was 19 months (maximum 124 months). Systemic disease progression occurred in 73% and was the leading cause of death in known cases, while intracranial disease recurred in 40%. The median PFS and OS were 21 and 19 months, respectively. The use of adjuvant WBRT correlated with improved PFS (HR 0.15, CI 0.0074–0.95, p = 0.044). Those who underwent surgery as primary modalities trended toward longer progression-free intervals (p = 0.095), although this did not reach significance.

Conclusions

Metastatic carcinoid disease to the brain appears to have a worse prognosis than that of other extracranial metastases. Although there was a trend toward a survival advantage in patients who underwent surgery and WBRT, further study is needed to establish definitive treatment recommendations.

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Deborah O. Heros and Roberto C. Heros

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Panagiotis Kerezoudis, Anshit Goyal, Ross C. Puffer, Ian F. Parney, Fredric B. Meyer, and Mohamad Bydon

OBJECTIVE

Acute traumatic subdural hematoma (atSDH) can be a life-threatening neurosurgical emergency that necessitates immediate evacuation. The elderly population can be particularly vulnerable to tearing bridging veins. The aim of this study was to evaluate inpatient morbidity and mortality, as well as predictors of inpatient mortality, in a national trauma database.

METHODS

The authors queried the 2016–2017 National Trauma Data Bank registry for patients aged 65 years and older who had undergone evacuation of atSDH. Patients were categorized into three age groups: 65–74, 75–84, and 85+ years. A multivariable logistic regression model was fitted for inpatient mortality adjusting for age group, sex, race, presenting Glasgow Coma Scale (GCS) category (3–8, 9–12, and 13–15), Injury Severity Score, presence of coagulopathy, presence of additional hemorrhages (epidural hematoma [EDH], intraparenchymal hematoma [IPH], and subarachnoid hemorrhage [SAH]), presence of midline shift > 5 mm, and pupillary reactivity (both, one, or none).

RESULTS

A total of 2508 patients (35% females) were analyzed. Age distribution was as follows: 990 patients at 65–74 years, 1096 at 75–84, and 422 at 85+. Midline shift > 5 mm was present in 72% of cases. With regard to additional hemorrhages, SAH was present in 21%, IPH in 10%, and EDH in 2%. Bilaterally reactive pupils were noted in 90% of patients. A major complication was observed in 14.4% of patients, and the overall mortality rate was 18.3%. In the multivariable analysis, the presenting GCS category was found to be the strongest predictor of postoperative inpatient mortality (3–8 vs 13–15: OR 3.63, 95% CI 2.68–4.92, p < 0.001; 9–12 vs 13–15: OR 2.64, 95% CI 1.79–3.90, p < 0.001; 30% of overall variation), followed by the presence of SAH (OR 2.86, 95% CI 2.21–3.70, p < 0.001; 25% of overall variation) and the presence of midline shift > 5 mm (OR 2.40, 95% CI 1.74–3.32, p < 0.001; 11% of overall variation). Model discrimination was excellent (c-index 0.81). Broken down by age decile group, mortality increased from 8.0% to 15.4% for GCS 13–15 to around 36% for GCS 9–12 to almost as high as 60% for GCS 3–8, particularly in those aged 85 years and older.

CONCLUSIONS

The present results from a national trauma database will, the authors hope, assist surgeons in preoperative discussions with patients and their families with regard to expected postoperative outcomes following surgical evacuation of an atSDH.

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Dileep D. Monie, Archis R. Bhandarkar, Ian F. Parney, Cristina Correia, Jann N. Sarkaria, Richard G. Vile, and Hu Li

Oncolytic viruses (OVs) are a class of immunotherapeutic agents with promising preclinical results for the treatment of glioblastoma (GBM) but have shown limited success in recent clinical trials. Advanced bioengineering principles from disciplines such as synthetic and systems biology are needed to overcome the current challenges faced in developing effective OV-based immunotherapies for GBMs, including off-target effects and poor clinical responses. Synthetic biology is an emerging field that focuses on the development of synthetic DNA constructs that encode networks of genes and proteins (synthetic genetic circuits) to perform novel functions, whereas systems biology is an analytical framework that enables the study of complex interactions between host pathways and these synthetic genetic circuits. In this review, the authors summarize synthetic and systems biology concepts for developing programmable, logic-based OVs to treat GBMs. Programmable OVs can increase selectivity for tumor cells and enhance the local immunological response using synthetic genetic circuits. The authors discuss key principles for developing programmable OV-based immunotherapies, including how to 1) select an appropriate chassis, a vector that carries a synthetic genetic circuit, and 2) design a synthetic genetic circuit that can be programmed to sense key signals in the GBM microenvironment and trigger release of a therapeutic payload. To illustrate these principles, some original laboratory data are included, highlighting the need for systems biology studies, as well as some preliminary network analyses in preparation for synthetic biology applications. Examples from the literature of state-of-the-art synthetic genetic circuits that can be packaged into leading candidate OV chassis are also surveyed and discussed.

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Shota Tanaka, Fredric B. Meyer, Jan C. Buckner, Joon H. Uhm, Elizabeth S. Yan, and Ian F. Parney

Object

Optimum management for elderly patients with newly diagnosed glioblastoma (GBM) in the temozolomide (TMZ) era is not well defined. The object of this study was to clarify outcomes in this population.

Methods

The authors retrospectively reviewed 105 consecutive cases involving elderly patients (age ≥ 65 years) with newly diagnosed GBM who were treated at the Mayo Clinic between 2003 and 2008.

Results

The patients' median age was 74 years (range 66–87 years), and the median Karnofsky Performance Status (KPS) score was 80 (range 40–90). Half of the patients underwent biopsy and half underwent resection. Patients with deep-seated lesions (19 patients [18%]) or multifocal lesions (34 patients [32%]) were more likely to have biopsy than resection (p = 0.0001 and 0.0009, respectively). New persistent neurological deficits developed in 7 patients (6.7%). Postoperative hemorrhage occurred in 6 patients (5.7%), all of whom underwent biopsy. Complete follow-up data regarding adjuvant treatment was available in 84 patients. Forty-one (49%) were treated with chemotherapy (mostly TMZ) and radiation therapy (RT), and 23 (27%) with RT alone. Nineteen (23%) received only palliative care after surgery (more common with biopsy, p = 0.03). Chemotherapy complications occurred in 28.6% (Grade 3 or 4 hematological complications in 11.9%). The median values for progression-free survival (PFS) and overall survival (OS) were 3.5 and 5.5 months. In a multivariate analysis, younger age (p = 0.03, risk ratio [RR] 0.34, 95% CI 0.13–0.89), single lesion (p = 0.02, RR 0.51, 95% CI 0.30–0.89), resection (p = 0.04, RR 0.54, 95% CI 0.31–0.94), and adjuvant treatment (p = 0.0001, RR 0.24, 95% CI 0.11–0.49) were associated with better OS. Only adjuvant treatment was significantly associated with prolonged PFS (p = 0.0007, RR 0.27, 95% CI 0.13–0.57). With combined therapy with resection, RT, and chemotherapy, the median PFS and OS were 8 and 12.5 months, respectively.

Conclusions

The prognosis for GBM worsens with increasing age in elderly patients. With important risks, resection and adjuvant treatment are associated with prolonged survival. Although selection bias cannot be excluded in this retrospective study, advanced age alone should not necessarily preclude optimal resection followed by adjuvant radiochemotherapy.

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Christopher S. Graffeo, Michael J. Link, Scott L. Stafford, Ian F. Parney, Robert L. Foote, and Bruce E. Pollock

OBJECTIVE

Stereotactic radiosurgery (SRS) is an accepted treatment option for patients with benign parasellar tumors. Here, the authors’ objective was to determine the risk of developing new or progressive internal carotid artery (ICA) stenosis or occlusion after single-fraction SRS for cavernous sinus meningioma (CSM) or growth hormone–secreting pituitary adenoma (GHPA).

METHODS

The authors queried their prospectively maintained registry for patients treated with single-fraction SRS for CSM or GHPA in the period from 1990 to 2015. Study criteria included no prior irradiation and ≥ 12 months of post-SRS radiological follow-up. Pre-SRS grading of ICA involvement was applied according to the 1993 classification schemes of Hirsch for CSM or Knosp for GHPA.

RESULTS

The authors conducted a retrospective review of 283 patients, 155 with CSMs and 128 with GHPAs. Ninety-three (60%) CSMs were Hirsch category 2 and 3 tumors; 97 (76%) GHPAs were Knosp grade 2–4 tumors. Median follow-up after SRS was 6.6 years (IQR 1–24.9 years). No GHPA or category 1 CSM developed ICA stenosis or occlusion. Three (5.2%) patients with category 2 CSMs had asymptomatic ICA stenosis (n = 2) or occlusion (n = 1); 1 (1.1%) category 2 CSM patient had transient ischemic symptoms. Five (14.3%) category 3 CSMs progressed to ICA occlusion (4 asymptomatic, 1 symptomatic). The median time to stenosis/occlusion was 4.8 years (IQR 1.8–7.6). Five- and 10-year risks of ICA stenosis/occlusion in category 2 and 3 CSM patients were 7.5% and 12.4%, respectively. Five- and 10-year risks of ischemic stroke from ICA stenosis/occlusion in category 2 and 3 CSM patients were both 1.2%. Multivariate analysis showed patient age (HR 0.92, 95% CI 0.86–0.98, p = 0.01), meningioma pathology (HR and 95% CI not defined, p = 0.03), and pre-SRS carotid category (HR 4.51, 95% CI 1.77–14.61, p = 0.004) to be associated with ICA stenosis/occlusion. Internal carotid artery stenosis/occlusion was not related to post-SRS tumor growth (HR and 95% CI not defined, p = 0.41).

CONCLUSIONS

New or progressive ICA stenosis/occlusion was common after SRS for CSM but was not observed after SRS for GHPA, suggesting a tumor-specific mechanism unrelated to radiation dose. Pre-SRS ICA encasement or constriction increases the risk of ICA stenosis/occlusion; however, the risk of ischemic complications is very low.

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Justin S. Smith, Ian F. Parney, Kathleen R. Lamborn, Michael W. McDermott, Penny K. Sneed, and Susan M. Chang

Object

This study was designed to assess the presentation, management, and outcome of cases involving patients who had a supratentorial glioma that subsequently progressed in the posterior fossa (PF).

Methods

The authors performed a retrospective chart review of adult patients treated between 1997 and 2005 for supratentorial gliomas that progressed in the PF. The 29 patients with PF progression in this study were relatively young (median age of 34 years at original presentation). Twenty of these patients presented with symptoms. The symptoms were typically nonspecific to this population, at times leading to delays in diagnosis. Overall, these symptoms resolved in eight patients (40%) and progressed or remained unchanged in 12 (60%). Patients treated with more than 5000 cGy of radiation administered to the PF were more likely to have symptom resolution than those who received any other form of treatment, including reduced doses of radiation (p = 0.004). The patients treated with higher doses also survived significantly longer after PF progression (univariate analysis, p = 0.01, and after adjusting for tumor grade, p = 0.04).

Conclusions

Patients with PF progression of supratentorial infiltrative gliomas may benefit from treatment, and the authors recommend more than 5000 cGy of radiation to the PF if prior radiotherapy ports and doses allow.