✓ The authors report on the technique and results of stereotactic biopsy for intrinsic lateral pontine and medial cerebellar lesions via a contralateral, transfrontal, extraventricular approach. Multiplanar stereotactic magnetic resonance imaging was used to plan an intraparenchymal approach, thus limiting the number of crossed pial surfaces to one and eliminating the need to cross ependymal surfaces. After the administration of a local anesthetic agent with light intravenous sedation, six patients harboring intrinsic lateral pontine lesions underwent biopsies via this intraparenchymal approach with 100% diagnostic yield and no operative morbidity. In comparison to the ipsilateral transfrontal approach, the contralateral approach laterally expands the infratentorial area accessible during biopsy to include the lateral pons and middle cerebellar peduncle. The contralateral, transfrontal, extraventricular approach is a useful, straight-forward and safe alternative to the suboccipital transcerebellar and ipsilateral, transfrontal, transtentorial routes for reaching lesions of the lateral pons and middle cerebellar peduncle.
Eric W. Amundson, Matthew J. McGirt and Alessandro Olivi
Kaisorn Chaichana, Scott Parker, Alessandro Olivi and Alfredo Quiñones-Hinojosa
Glioblastoma multiforme (GBM) is the most common and aggressive type of primary brain tumor in adults. Although the average survival is ~ 12 months, individual survival is heterogeneous. The ability to predict short- and long-term survivors is limited. Therefore, the aims of this study were to ascertain preoperative risk factors associated with survival, develop a preoperative prognostic grading system, and evaluate the utility of this grading system in predicting survival for patients undergoing resection of a primary intracranial GBM.
Cases involving adult patients who underwent surgery for an intracranial primary (de novo) GBM between 1997 and 2007 at The Johns Hopkins Hospital, an academic tertiary-care institution, were retrospectively reviewed. Multivariate proportional hazards regression analysis was used to identify preoperative factors associated with survival, after controlling for extent of resection and adjuvant therapies. The identified associations with survival were then used to develop a grading system based on preoperative variables. Survival as a function of time was plotted using the Kaplan-Meier method, and survival rates were compared using Log-rank analysis. Associations with p < 0.05 were considered statistically significant.
Of the 393 patients in this study, 310 (79%) had died as of most recent follow-up (median time from surgery to death 11.9 months). The preoperative factors, independent of extent of resection and adjuvant therapies (carmustine wafers, temozolomide, and radiation), found to be negatively associated with survival were: age > 60 years (p < 0.0001), Karnofsky performance status score ≤ 80 (p < 0.0001), motor deficit (p = 0.02), language deficit (p = 0.001), and periventricular tumor location (p = 0.04). Patients possessing 0–1, 2, 3, and 4–5 of these variables were assigned a preoperative grade of 1, 2, 3, and 4, respectively. Patients with a preoperative grade of 1, 2, 3, and 4 had a median survival of 16.6, 10.2, 6.8, and 6.1 months, respectively.
The present study found that older age, poor performance status, motor deficit, language deficit, and periventricular tumor location independently predicted poorer survival in patients undergoing GBM resection. A grading system based on these factors was able to identify 4 distinct groups of patients with different survival rates. This grading system, based only on preoperative variables, may provide patients and physicians with prognostic information that may guide medical and surgical therapy before any intervention is pursued.
Kaisorn L. Chaichana, Scott L. Parker, Alessandro Olivi and Alfredo Quiñones-Hinojosa
Seizures are a common presenting symptom and cause of morbidity for patients with malignant astrocytomas. The authors set out to determine preoperative seizure characteristics, effects of surgery on seizure control, and factors associated with prolonged seizure control in patients with malignant astrocytomas.
Cases involving adult patients who underwent primary resection of a hemispheric anaplastic astrocytoma (AA) or glioblastoma multiforme (GBM) at the Johns Hopkins Medical Institutions between 1996 and 2006 were retrospectively reviewed. Multivariate logistical regression analysis was used to identify associations with pre-operative seizures, and multivariate proportional hazards regression analyses were used to identify associations with prolonged seizure control following resection.
Of the 648 patients (505 with GBM, 143 with AA) in this series, 153 (24%) presented with seizures. The factors more commonly associated with preoperative seizures were AA pathology (p = 0.03), temporal lobe involvement (p = 0.04), and cortical location (p = 0.04), while the factors less commonly associated with preoperative seizures were greater age (p = 0.03) and larger tumor size (p ≤ 0.001). Among those patients with a history of seizures, outcome 12 months after surgery was Engel Class I (seizure free) in 77%, Class II (rare seizures) in 12%, Class III (meaningful improvement) in 6%, and Class IV (no improvement) in 5%. Postoperative seizures were rare in patients without a history of preoperative seizures. The factor positively associated with prolonged seizure control was increased Karnofsky Performance Scale score (p = 0.002), while the factors negatively associated with seizure control were preoperative uncontrolled seizures (p = 0.03) and parietal lobe involvement (p = 0.005). Seizure recurrence in patients with postoperative seizure control was independently associated with tumor recurrence (p = 0.006).
The identification and consideration of factors associated with prolonged seizure control may help guide treatment strategies aimed at improving the quality of life for patients with malignant astrocytomas.
Synovitis, acne, pustulosis, hyperostosis, and osteitis syndrome presenting as a primary calvarial lesion
Case report and review of the literature
Francesco Dimeco, Richard E. Clatterbuck, Khan W. Li, Edward F. McCarthy and Alessandro Olivi
✓ The synovitis, acne, pustulosis, hyperostosis, and osteitis (SAPHO) syndrome is a recently described, currently evolving clinical entity that groups together several idiopathic disorders of bone and skin formerly described under a variety of names. Among the spectrum of possible locations for the bone lesions, there is no previous report in the literature of primary involvement of the skull vault. A patient with primary involvement of the calvaria in the setting of SAPHO syndrome is described here, which, to the authors' knowledge, is the first report of such localization. The clinically and radiologically benign evolution of the different stages of the bone lesions is presented. The authors suggest that the SAPHO syndrome should be considered in the differential diagnosis of lytic, sclerotic, or hyperostotic lesions of the skull, particularly before considering invasive diagnostic procedures.
Francesco DiMeco, Khan W. Li, Betty M. Tyler, Ariel S. Wolf, Henry Brem and Alessandro Olivi
Object. Mitoxantrone is a drug with potent in vitro activity against malignant brain tumor cell lines; however, its effectiveness as a systemic agent has been hampered by poor central nervous system penetration and dose-limiting myelosuppression. To avoid these problems, we incorporated mitoxantrone into biodegradable polymeric wafers to be used for intracranial implantation, a strategy that has been shown to be safe and successful in the treatment of malignant gliomas. The authors investigated the release kinetics, toxicity, distribution, and efficacy of mitoxantrone delivered from intracranially implanted biodegradable wafers in the treatment of 9L gliosarcoma in Fischer 344 rats.
Methods. Mitoxantrone released from the biodegradable wafer matrix reached therapeutic drug concentrations in the brain for at least 35 days. Only animals with implanted wafers of the highest drug loading dose (20% mitoxantrone by weight) showed signs of significant toxicity. In three separate efficacy experiments, animals treated with mitoxantrone-loaded biodegradable wafers had significantly improved survival compared with control animals. The combined median survival for each treatment group was the following: 0% mitoxantrone wafers, 19 days; 1%, 30 days, p < 0.0001; 5%, 34 days, p < 0.0001; and 10%, 50 days, p < 0.0001.
Conclusions. These findings establish that mitoxantrone delivered from intracranially implanted biodegradable wafers is effective in the treatment of malignant gliomas in rodents and should be considered for future clinical application in humans.
Matthew A. Koenig, Romergryko G. Geocadin, Piotr Kulesza, Alessandro Olivi and Henry Brem
✓ Rhabdoid meningioma (RM) is a recently described, aggressive variant of meningioma. The authors report a case of RM occurring in the resection cavity of an unrelated neurosurgical procedure, temporal lobectomy for intractable seizures. The patient presented with intractable headache 10 years after the temporal lobectomy. Imaging revealed a dura-based, uniformly enhancing lesion within the resection cavity. She underwent gross-total resection and the findings of the surgical pathological report were consistent with an RM, with a dramatically elevated MIB-1 index of approximately 50%. The patient's clinical course was complicated by severe pain and communicating hydrocephalus secondary to rapid dissemination of malignant cells throughout the CSF pathways. Despite aggressive measures, including tumor resection, ventriculoperitoneal shunt placement, and the initiation of conventional radiation therapy, the ensuing leptomeningeal carcinomatosis proved to be rapidly fatal.
Kaisorn L. Chaichana, Thomas Kosztowski, Ashwini Niranjan, Alessandro Olivi, Jon D. Weingart, John Laterra, Henry Brem and Alfredo Quiñones-Hinojosa
Patients harboring anaplastic astrocytomas (AAs) typically have a poor prognosis, with median survival times of approximately 3 years following resection. However, a significant variability in individual outcomes remains, with some patients surviving for a few months and others for several years. The ability to predict patient outcomes based on preoperative variables would help prognosticate survival and may also guide treatment strategies. The prognostic implications of a preoperative contrast-enhancing AA remain poorly understood.
The medical records of all patients who underwent a craniotomy for a hemispheric AA from 1996 to 2006 at a single institution were retrospectively reviewed. Multivariate proportional hazards regression analysis was used to identify independent associations with recurrence and survival. The Kaplan-Meier method and log-rank analysis were used to plot and compare outcomes for patients with and without preoperative contrast enhancement.
One hundred sixty-five patients were available for analysis. The AAs were contrast enhancing in 102 patients (62%), and nonenhancing in 63 patients (38%). There were no significant differences in clinical and treatment-related variables between patients with and without contrast enhancement. After multivariate analysis, contrast enhancement was independently associated with decreased survival (p = 0.02) and increased recurrence (p = 0.04). The 5-year overall survival rates for patients with contrast-enhancing versus nonenhancing tumors were 31 and 38.5%, respectively. The 3-year rates of progression-free survival for patients with contrast-enhancing versus nonenhancing tumors were 32 and 56%, respectively. Interestingly, heterogeneously enhancing tumors appear to result in poorer outcomes as compared with other types of enhancement (such as ring enhancing, nodular, and others). Among patients with contrast-enhancing AAs, gross-total resection significantly delayed recurrence (p = 0.05) but did not significantly prolong survival (p = 0.52).
This study may provide insights into risk-stratifying patients with AAs, and most specifically those with AAs that enhance with contrast administration.
Kevin D. Judy, Alessandro Olivi, Kwame G. Buahin, Abraham Domb, Jonathan I. Epstein, O. Michael Colvin and Henry Brem
✓ Most malignant gliomas grow despite treatment by standard chemotherapeutic agents. The authors explored the use of an innovative drug, 4-hydroperoxycyclophosphamide (4HC), delivered via a controlled-release biodegradable polymer to determine whether local delivery would enhance efficacy. This drug is an alkylator-type chemotherapeutic agent derived from cyclophosphamide. Unlike the parent drug, which requires activation by hepatic microsomes, 4HC is active in vitro. Two rat glioma cell lines, 9L and F98, were treated in cell culture with medium containing 4HC. Both cell lines were more sensitive to 4HC than to a nitrosourea, BCNU, an agent of established value in the local therapy of gliomas.
Ninety Fischer 344 rats implanted with 9L or F98 gliomas were treated with an intracranial polymer implant containing 0% to 50% loaded 4HC in the polymer, and it was found that 20% 4HC—loaded polymers caused minimum local brain toxicity and maximum survival. These polymers were then used to compare the in vivo efficacy of 4HC to BCNU in rats implanted with 9L glioma. Animals with brain tumors treated with 4HC had a median survival span of 77 days compared to the median survival of 21 days in BCNU-treated animals and median survival of 14 days in untreated animals. Long-term survival for more than 80 days was 40% in the 4HC-treated rats versus 30% in the BCNU-treated rats.
The polymer carrier used in this study was a copolyanhydride of dimer erucic acid and sebacic acid 1:1, which was able to maintain the hydrolytically unstable 4HC in a stable state for local delivery. Thus, it is concluded that 4HC-impregnated polymers provide an effective and safe local treatment for rat glioma.
Henry Brem, Rafael J. Tamargo, Alessandro Olivi, Michael Pinn, Jon D. Weingart, Moody Wharam and Jonathan I. Epstein
✓ Sustained drug delivery by biodegradable polymer devices can increase the therapeutic efficacy of drugs by producing high local tissue concentrations over extended periods of time. It has been shown previously that implantation of controlled-release polymers impregnated with the nitrosourea carmustine (BCNU) extended the period of survival in rats bearing the 9L glioma compared with similar rats treated with systemically administered BCNU. This study evaluated the effect on the monkey brain of interstitial delivery of BCNU by the biodegradable polyanhydride copolymer poly[bis(p-carboxyphenoxy)propane]anhydride (PCPP) and sebacic acid (SA) in a 20:80 formulation (PCPP:SA). The effect of combining interstitial BCNU with radiation therapy was also evaluated. Eighteen male cynomologus monkeys were randomly assigned to one of four groups: a control group; a group with implantation of empty polymer; a group with implantation of BCNU-loaded polymer; and a group with implantation of empty polymer in the right hemisphere and BCNU-loaded polymer in the left hemisphere, followed by irradiation. The effects were evaluated radiologically and histologically at specified times. A local reaction by the brain to the polymer was found, which was greater when the polymer contained BCNU. Local cerebral edema was observed radiographically on postoperative Day 14 and had resolved by Day 72. Histologically, a subacute cellular inflammatory response was seen on postoperative Day 16, which had changed to a chronic inflammatory response by Day 72. In the group with radiation therapy administered to the hemisphere bearing BCNU-loaded polymer, only localized pathological changes were detected. In all animals, brain distant from the polymer implantation site was normal. No neurological or general deleterious effects were seen in any of the animals. It is concluded that the interstitial delivery of BCNU by the polyanhydride polymer PCPP:SA is safe in the primate brain and that concomitant radiation therapy did not lead to any adverse effects. These experimental findings are important to an understanding of the clinical effects of PCPP:SA implants in treating brain diseases.
Kaisorn L. Chaichana, Matthew J. McGirt, John Laterra, Alessandro Olivi and Alfredo Quiñones-Hinojosa
Unlike their malignant counterparts, low-grade gliomas are associated with prolonged survival. However, these tumors have a propensity to progress after resection and ultimately undergo malignant degeneration. The factors associated with recurrence and malignant degeneration remain relatively unknown. The authors set out to determine factors that were independently associated with recurrence and malignant degeneration in patients who underwent resection of a hemispheric low-grade glioma.
Adult patients who underwent craniotomy and resection of a hemispheric low-grade glioma (WHO Grade II) at the Johns Hopkins Medical Institution's academic tertiary-care institution between 1996 and 2006 were retrospectively reviewed. Multivariate proportional hazards regression analyses were used to identify associations with tumor recurrence and malignant degeneration.
Of the 191 consecutive patients with low-grade gliomas in this series (89 fibrillary astrocytomas, 89 oligodendrogliomas, and 13 mixed gliomas), 83 (43%) and 44 (23%) experienced tumor recurrence and malignant degeneration at last follow-up, respectively. The 5-year progression-free and malignancy-free survival rates were 44 and 74%, respectively. Independent predictors of recurrence were duration of longest lasting symptom (relative risk [RR] 0.978, 95% CI 0.954–0.996, p = 0.01), tumor size (RR 1.328, 95% CI 1.109–1.602, p = 0.002), and preoperative contrast enhancement (RR 2.558, 95% CI 1.241–5.021, p = 0.01). Independent factors associated with malignant degeneration were fibrillary astrocytoma pathology (RR 1.800, 95% CI 1.008–4.928, p = 0.04), tumor size (RR 1.086, 95% CI 1.044–1.358, p = 0.04), and gross-total resection (RR 0.526, 95% CI 0.221–1.007, p = 0.05).
The identification and consideration of factors associated with recurrence and malignant progression may help guide treatment strategies aimed at delaying recurrence and preventing malignant degeneration for patients with hemispheric low-grade gliomas.