Timothy F. Witham

Morbidity and survival after 1,3-bis(2-chloroethyl)-1-nitrosourea wafer implantation for recurrent glioblastoma: a retrospective case-matched cohort series.

OBJECTIVE To determine the risks and survival benefit associated with implantation of an absorbable, 1,3-bis(2chloroethyl)-1-nitrosourea-impregnated polymer wafer, we prospectively studied patients with recurrent glioblastoma multiforme and compared them with a demographically matched cohort group. METHODS Over a 29-month period, 62 patients underwent operations. All had tumor growth despite standard treatment, a Karnofsky performance score of > or =70, and histopathological confirmation of glioblastoma. Seventeen patients underwent gross total resection with placement of 1,3-bis(2-chloroethyl)-1-nitrosourea wafers (wafer group) at a median 44 weeks from diagnosis (6 women, 11 men; median age, 56 years). A cohort group of 45 patients undergoing surgery for recurrent glioblastoma during the same time period, but not receiving wafers, was identified. Surgery was performed at a median 47 weeks from diagnosis (14 women, 31 men; median age, 54 years). RESULTS Within 6 weeks of surgery, 13 complications were identified in 8 patients in the wafer group. In the cohort group, 6 patients sustained 8 complications. We were unable to identify any survival advantage using Kaplan-Meier analysis. In the wafer group, median survival was 58 weeks from diagnosis and 14 weeks from wafer implantation. In the cohort group, median survival was 97 weeks from diagnosis and 50 weeks from operation. CONCLUSION 1,3-bis(2-chloroethyl)-1-Nitrosourea wafer implantation for recurrent glioblastoma was associated with a higher risk of postoperative complications, particularly those related to infection and wound healing. No clear survival benefit associated with wafer implantation was identified.

Autologous Glioma Cell Vaccine Admixed with Interleukin-4 Gene Transfected Fibroblasts in the Treatment of Recurrent Glioblastoma: Preliminary Observations in a Patient with a Favorable Response to Therapy

We designed a phase I clinical trial of vaccinations with autologous glioma cells expressing transgene-derived interleukin-4 (IL-4), and treated one patient with a right temporal lobe recurrent glioblastoma. This 62-year-old man underwent craniotomy and partial tumor removal, at which time autologous tumor cells were obtained for vaccine preparation. After confirming the patients cellular immune function by skin test, two cycles of vaccination with irradiated autologous glioma cells admixed with gene transfected fibroblasts were given intradermally. The patient demonstrated no evidence of allergic encephalitis throughout this course. Immunohistochemistry with biopsy samples taken from the vaccine sites demonstrated that the infiltration level of CD4, CD8 and CD1a positive cells increased proportionally to the amount of IL-4 produced at the each site, suggesting that there was local immune response induced at the vaccine site. While it is premature to assess effectiveness of the vaccine, this initial patients course suggested a transient response to the vaccine, and he survived 10 months after treatment.

Survival of patients with high grade glioma treated with intrathecal thiotriethylenephosphoramide for ependymal or leptomeningeal gliomatosis

The diagnosis of leptomeningeal dissemination of malignant glioma (meningeal gliomatosis) is associated with poor survival. Intrathecal (IT) chemotherapeutic agents used to achieve tumor control and improve survival include methotrexate, cytosine arabinoside (ara‐C), thiotriethylenephosphoramide (thio‐TEPA), neocarzinostatin, and 3‐[(4‐amino‐2‐methyl‐5‐pyrimidinyl)methyl]‐1‐(2‐chloroethyl)‐1‐nitrosourea hydrochloride (ACNU). Little information exists about survival following administration of IT chemotherapy. The authors report survival data from a series of patients with supratentorial anaplastic astrocytoma (AA) or glioblastoma multiforme (GBM) treated for ependymal or leptomeningeal gliomatosis with IT thio‐TEPA.

The Characterization of Tumor Apoptosis after Experimental Radiosurgery

We sought to evaluate whether radiosurgery induces apoptosis in an experimental glioma model and to elucidate the time course of this radiobiologic phenomenon. Fischer 344 rats harboring established intracranial 9L gliosarcomas underwent radiosurgery (n = 42) or no radiosurgery (n = 45). Animals were sacrificed at 3, 6, 12, 24, 48, 72 h, and 1 or 2 weeks after treatment and in situ tumor apoptosis was assessed by specific staining. Tumor apoptosis was noted to be statistically higher in radiosurgery-treated animals relative to controls at the 6-, 24-, and 48-hour time points following radiosurgery. Radiosurgery induces apoptosis in the rat intracranial 9L gliosarcoma in a time-dependent fashion. The time course of this radiobiologic phenomenon begins at approximately 6 h following radiosurgery, continues up to 48 h, and begins to decline by 72 h.

7-Hydroxystaurosporine-induced Apoptosis in 9L Glioma Cells Provides an Effective Antigen Source for Dendritic Cells and Yields a Potent Vaccine Strategy in an Intracranial Glioma Model

OBJECTIVE On the basis of recent studies indicating that tumoral apoptotic bodies may provide a potent source of antigen for delivery to antigen-presenting cells, as well as observations that signal transduction modulation may constitute a promising approach for inducing glioma cell apoptosis, we explored the efficacy of vaccination with glioma apoptotic body-pulsed dendritic cells (DCs) for inhibiting tumor growth in the syngeneic 9L glioma/Fischer rat model. METHODS For induction of apoptosis, 7-hydroxystaurosporine (UCN-01) (200–300 ng/ml), a selective protein kinase C inhibitor, was co-incubated with 9L cells in vitro for 72 or 96 hours. After this pretreatment period, glioma cells and DCs were mixed, and the interaction between DCs and apoptotic 9L tumor cells was assessed using two-color flow cytometry. In a series of experiments, the efficacy of vaccination strategies using DCs co-cultured with apoptotic 9L cells was then examined in animals harboring intracranial tumors. RESULTS Pretreatment of 9L cells with UCN-01 resulted in approximately 50% of cells’ being observed to undergo apoptosis as compared with less than 3% of controls. After subsequent co-culture, two-color flow cytometry demonstrated a time-dependent physical association of DCs with the apoptotic glioma cells. Survival in animals harboring intracranial tumors was significantly longer for the animals treated with a glioma apoptotic body-pulsed DC vaccine than in the animals that received apoptotic glioma cells and DCs alone or vehicle (i.e., the controls), especially those that underwent a sequential vaccination strategy (P < 0.0001). Long-term survival (>90 d) was demonstrated in 6 (75%) of 8 animals that underwent this vaccination approach versus 0 (0%) of 16 controls. In contrast, no survival benefit was observed in animals that received DCs that were co-cultured with vehicle-treated (nonapoptotic) 9L cells. Three of four long-term survivors that were rechallenged intracranially with tumor cells also survived over the long term. CONCLUSION These studies suggest that induction of apoptosis in glioma cells by use of UCN-01 may promote the uptake of tumor antigens by DCs. This finding is important because apoptotic body-stimulated DCs may hold promise in promoting a host response against an established intracranial glioma, particularly if the parameters for apoptotic induction, duration of co-culture, and vaccination can be optimized.

Expression of a Soluble Transforming Growth Factor-β (TGFβ) receptor reduces tumorigenicity by regulating natural killer (NK) cell activity against 9L gliosarcoma in vivo

Immunotherapy of gliomas has been forwarded as an attractive alternative to standard therapeutic modalities. Numerous observations indicate some therapeutic efficacy with this approach, but it is not curative in most reports. It is well established that gliomas suppress immune reactivity via a number of mechanisms, including expression CD95 ligand (CD95L), which induces apoptosis of immune effector cells, and secretion of immunosuppressive factors such as transforming growth factor-beta (TGFβ). It has been hypothesized that abrogation of production or function of TGFβ would improve immune reactivity to gliomas. To investigate this in a fashion that is translatable into clinical practice, we utilized a retroviral vector encoding a truncated, soluble form of the Type II receptor for TGFβ (TFGβsr) and expressed it in the rat 9L gliosarcoma line (9L-TGFβsr). We then determined whether expression of TGFβsr affected in vitro sensitivity of 9L to lysis by immune effector cells, whether expression of TGFβsr affected tumorigenesis of 9L in vivo, and whether TGFβsr affected expression of immunity to 9L. In these experiments, we determined that 9L-TGFβsr was more susceptible than sham transfected 9L (9L-neo) to lysis by natural killer (NK) cells. We also determined that subcutaneously implanted 9L-TGFβsr was less tumorigenic than 9L-neo in syngeneic rats. Similarly, survival was extended by ∼40% in rats given intracranial 9L-TGFβsr compared to 9L-neo. Finally, we determined that elimination of CD161+ cells resulted in comparable growth of 9L-neo and 9L-TGFβsr in vivo, indicating that NK or NK-like cells were responsible for the anti-tumor effects in this model.

Relationship Between Type of Health Insurance and Time to Inpatient Rehabilitation Placement for Surgical Subspecialty Patients

A significant proportion of patients on a neurosurgical service require inpatient rehabilitation placement after discharge. The relationship between the type of health insurance of the patient at the time of admission and the time to placement of patients has not previously been addressed. We prospectively studied all patients on the adult neurosurgical service at our hospital to determine whether the type of health insurance carried by patients is related to the time necessary to arrange acceptance into inpatient rehabilitation facilities. Ninety-one patients (51 men, 40 women; mean age, 56 years) admitted to the neurosurgery service during a 6-month period required inpatient rehabilitation placement after discharge. The time in days between the request for placement into a rehabilitation facility and the acceptance of the patient was examined. The mean time for placement of patients with and without health insurance at the time of admission was 0.8 days and 2.1 days, respectively (overall mean, 1.1 days) (P < .002). No statistically significant associations were found between age, sex, or race of the patient and the time to placement. In addition, there was no difference in the time to placement between those patients admitted as a result of trauma and those patients admitted for reasons other than trauma. These results indicate that among patients on a neurosurgical service, patients with private health insurance are accepted into inpatient rehabilitation approximately 1 day sooner than patients without private health insurance. Patients without private health insurance are delayed in their transfer to inpatient rehabilitation facilities and more aggressive inpatient rehabilitation. How this finding translates into an increase in cost of care or a decrease in patient outcomes is unknown.

The role of stereotactic cyst aspiration for glial and metastatic brain tumors.

OBJECTIVE To evaluate the role of stereotactic cyst aspiration in the context of multimodality management of cystic glial and metastatic tumors, we retrospectively reviewed our experience with 38 patients during a 10-year interval. METHODS All 38 patients had one or more computed tomography or magnetic resonance imaging guided stereotactic cyst aspirations. Twenty-seven patients had glial neoplasms and 11 had metastatic brain tumors. Twenty-two patients underwent cyst aspiration as the initial treatment modality while 15 patients had cyst aspiration following previous treatments. RESULTS In the immediate postoperative period, 19 of the 27 (70%) patients with gliomas and nine of the 11 (82%) patients with metastatic tumors experienced symptomatic improvement. No procedure-related morbidity was encountered. Twelve patients (31.5%) eventually required a catheter-reservoir system. Thirty-seven percent of patients with cystic glial neoplasms and 18% of patients with metastatic tumors had delayed cytoreductive surgery by craniotomy subsequent to stereotactic cyst aspiration. Reduction in tumor volume following aspiration facilitated Gamma knife radiosurgery in seven patients. CONCLUSION Single stereotactic aspiration is a low risk procedure that provides immediate relief of symptoms in patients with cystic brain tumors. It appears to be valuable together with the use of other therapeutic strategies.

Local secretion of a soluble TGF-β receptor reverses glioma-mediated inhibition of NK cells in the rat 9L glioma model

cele (MMC) support a ‘two-hit‘ hypothesis for postnatal neurologic deficits, with a primary developmental abnormality followed by a secondary insult. The exact mechanism by which this secondary injury occurs remains poorly elucidated. Possible etiologies include chemical injury secondary to amniotic fluid exposure, direct intrauterine trauma to the spinal cord, and mechanical cord stretching by hydrodymanic pressure in the subarachnoid space. With careful histologic evaluation of pathologic specimens, the impact of the in utero environment on neural development and the response to secondary injury may be better assessed.