Biomedical subjects

Jon Weingart

Publications and source records attributed to Jon Weingart.

9 recordsLinked to original sources

PubMed2006

Interstitial chemotherapy for malignant gliomas: the Johns Hopkins experience.

Malignant gliomas are very difficult neoplasms for clinicians to treat. The reason for this is multifaceted. Many treatments that are effective for systemic cancer are unable to cross the blood-brain barrier and/or have unacceptable systemic toxicities. Consequently, in recent years an effort has been placed on trying to develop innovative local treatments that bypass the blood-brain barrier and allow for direct treatment in the central nervous system (CNS)-interstitial treatment. In this paper, we present our extensive experience in using interstitial chemotherapy as a strategy to treat malignant brain tumors at a single institution (The Johns Hopkins Hospital). We provide a comprehensive summary of our preclinical work on interstitial chemotherapy at the Hunterian Neurosurgery Laboratory, reviewing data on rat, rabbit, and monkey studies. Additionally, we present our clinical experience with randomized placebo-controlled studies for the treatment of malignant gliomas. We compare survival statistics for those patients who received placebo versus Gliadel as initial therapy (11.6 months vs. 13.9 months, respectively) and at the time of tumor recurrence (23 weeks vs. and 31 weeks, respectively). We also discuss the positive impact of local therapy in avoiding the toxicities associated with systemic treatments. Furthermore, we provide an overview of newer chemotherapeutic agents and other strategies used in interstitial treatment. Finally, we offer insight into some of the lessons we have learned from our unique perspective.

Animals↗

PubMed2006

Adjustable vs set-pressure valves decrease the risk of proximal shunt obstruction in the treatment of pediatric hydrocephalus.

INTRODUCTION: The use of programmable shunt valves has increased dramatically in the practice of pediatric hydrocephalus. Despite theoretical advantages, it remains unclear if the use of programmable vs set-pressure valves affects shunt outcome. MATERIALS AND METHODS: The clinical and radiological records of all pediatric patients undergoing ventriculoperitoneal (VP), ventriculopleural (VPl), and ventriculoatrial (VA) shunt surgery from 2001 to 2004 at an academic institution were reviewed. The association of programmable vs set-pressure valves with subsequent shunt revision was assessed by Kaplan-Meier shunt survival plots and log-rank analysis. RESULTS: A total of 279 VP, VPl, and VA shunt surgeries were performed on patients with median (interquartile range) age of 4 (1-14) years (161 male, 118 female; 158 communicating, 122 obstructive hydrocephalus). Programmable valves were used in 76 (27%) cases and set-pressure valves in 203 (73%). At mean+/-SD follow-up of 17 +/- 13 months, programmable vs set-pressure valves were associated with reduced risk of both overall shunt revision [26 (35%) vs 109 (54%); relative risk (RR) (95% CI); 0.61 (0.41-0.91), p = 0.016] and proximal obstruction [9 (12%) vs 58 (28%); RR (95% CI); 0.39 (0.27-0.80), p = 0.006]. There was no difference in distal obstruction [3 (4%) vs 11 (5%) cases], infection [6 (8%) vs 12 (6%) cases], valve obstruction [0 (0%) vs 4 (2%)], or shunt disconnection [2 (3%) vs 1 (1%)] between adjustable and set-pressure valves, respectively. CONCLUSION: In our experience, the use of programmable vales was associated with a decreased risk of proximal shunt obstruction and shunt revision. Programmable valves may be preferred in patients frequently experiencing proximal shunt failure. A prospective, controlled study is warranted to evaluate the potential value of adjustable vs set-pressure valve systems.

Adolescent↗

PubMed2005

Phase I trial of temozolomide plus O6-benzylguanine for patients with recurrent or progressive malignant glioma.

PURPOSE: We conducted a two-phase clinical trial in patients with progressive malignant glioma (MG). The first phase of this trial was designed to determine the dose of O6-BG effective in producing complete depletion of tumor AGT activity for 48 hours. The second phase of the trial was designed to define the maximum tolerated dose (MTD) of a single dose of temozolomide when combined with O6-BG. In addition, plasma concentrations of O6-BG and O6-benzyl-8-oxoguanine were evaluated after O6-BG. PATIENTS AND METHODS: For our first phase of the clinical trial, patients were scheduled to undergo craniotomy for AGT determination after receiving a 1-hour O6-BG infusion at 120 mg/m2 followed by a continuous infusion at an initial dose of 30 mg/m2/d for 48 hours. The dose of the continuous infusion of O6-BG escalated until tumor AGT was depleted. Once the O6-BG dose was established a separate group of patients was enrolled in the second phase of clinical trial, in which temozolomide, administered as a single dose at the end of the 1-hour O6-BG infusion, was escalated until the MTD was determined. RESULTS: The O6-BG dose found to be effective in depleting tumor AGT activity at 48 hours was an IV bolus of 120 mg/m2 over 1 hour followed by a continuous infusion of 30 mg/m2/d for 48 hours. On enrolling 38 patients in six dose levels of temozolomide, the MTD was established at 472 mg/m2 with dose-limiting toxicities limited to myelosuppression. CONCLUSION: This study provides the foundation for a phase II trial of O6-BG plus temozolomide in temozolomide-resistant MG.

Adult↗

PubMed2004

Clinical course and pathologic findings after Gliadel and radiotherapy for newly diagnosed malignant glioma: implications for patient management.

Randomized trials have demonstrated Gliadel improves survival for appropriately selected patients with newly diagnosed malignant glioma. As only limited information is available to guide the management of patients who have Gliadel controlled-release BCNU wafers implanted in the cranial resection cavity prior to radiotherapy (RT), this retrospective review was conducted to describe clinical course, toxicity, and pathologic findings after this therapy for newly diagnosed malignant glioma. Forty-six consecutive patients receiving Gliadel (3.8% BCNU impregnated wafers) followed by radiotherapy for newly diagnosed malignant glioma at Johns Hopkins Hospital from 1990 to August 1999 were identified, although one was lost to follow up and is excluded. Patients were evaluated for postoperative infection, pathology at reoperation, and survival. Twenty-eight patients received radiotherapy at Johns Hopkins and these patients are also evaluable for toxicity experienced during and one month after completion of RT. The median age of all patients is 57 years. Eighty-nine percent had glioblastoma, and median follow-up of surviving glioblastoma patients is 16.8 (12-20) months. Postoperative infection or need for reoperation within 30 days was uncommon after Gliadel placement. Full-dose radiotherapy was tolerable after Gliadel implantation. Five patients (19%) developed neurologic symptoms during radiotherapy responding to increased steroids and/or anticonvulsants, whereas an additional 8 of 27 (30%) developed neurologic symptoms during dexamethasone taper that responded to increases in dexamethasone dose. At one month after RT, 58% of patients were still on dexamethasone despite attempted taper. Fifteen of 45 patients, 33% underwent reoperation or biopsy for a new local contrast-enhancing lesion. In five of 15 (33%) the reoperation revealed necrosis or treatment effect without active tumor. Two of five patients with treatment/effect necrosis has a third surgery 2.9 and 3.2 months after the initial reoperation, and treatment effect/necrosis without tumor was demonstrated in both cases. The Kaplan-Meier median survival for all the glioblastoma patients is 12.8 (95% CI 9.6, 15.9) months. For glioblastoma patients under 55 years old, median survival is 15.9 (95% CI 13.5, too few events) months whereas for older patients it is 9.6 (7.7, 14.4) months. We conclude that Gliadel followed by full-dose standard radiotherapy is acutely well tolerated, although, close supervision should be emphasized during dexamethasone taper. Median survival in excess of one year suggests that there are not complications that result in overall premature death. The finding of necrosis/treatment effect was noted in five of 45 (11%) of all patients and five of 15 (33%) of those undergoing reoperation. Therefore, the possibility of necrosis/treatment effect should be considered for each patient with radiographic findings suspicious for local recurrence.

Adult↗

PubMed2003

Surgical outcome following resection of contrast-enhanced pediatric brainstem gliomas.

BACKGROUND: The role of surgery in the management of gadolinium-enhancing pediatric brainstem lesions on magnetic resonance imaging (MRI) has been a matter of open debate. This clinical series correlates radiological and pathological findings to assess the role of contrast enhancement as an indication for surgery with respect to clinical outcome. METHODS: We retrospectively reviewed the charts of all pediatric patients admitted to the Johns Hopkins Hospital with a diagnosis of a brainstem tumor between January 1985 and December 2000. RESULTS: There were a total of 89 patients who met the inclusion criteria. Fifty-seven patients (64.0%) underwent surgical resection while 32 (36%) were treated with radiation and/or chemotherapy. Of the surgical candidates, 57 (100%) had an accompanying MRI scan significant for an enhancing lesion in the midbrain, pons or the medulla. The pathology was consistent with juvenile pilocytic astrocytoma in 30 patients (52.6%) and glioblastoma multiforme in 12 patients (21.1%). The remaining cases consisted of 10 patients (17.5%) with fibrillary astrocytomas, 3 (5.3%) with gangliogliomas, 1 (1.8%) with an oligodendroglioma and 1 (1.8%) with a primitive neuroectodermal tumor. A total of 29 patients had a total surgical resection, 8 a near total resection (>90%), 15 a subtotal resection (50-90%) and 5 a partial resection (<50%). The progression-free survival of all patients was 71.9% at 3 years and 45.6% at 5 years. CONCLUSIONS: This case series illustrates that contrast-enhanced MRI has positive prognostic value in the management of pediatric brainstem gliomas. In our study, the majority of enhancing tumors were low grade and amenable to surgical intervention. Consequently, we recommend surgical resection and pathological diagnosis of all enhancing brainstem tumors with adjuvant therapy reserved for recurrent or unresectable cases.

Adolescent↗

PubMed2003

An inflatable balloon catheter and liquid 125I radiation source (GliaSite Radiation Therapy System) for treatment of recurrent malignant glioma: multicenter safety and feasibility trial.

OBJECT: In this study the authors evaluated the safety and performance of the GliaSite Radiation Therapy System (RTS) in patients with recurrent malignant brain tumors who were undergoing tumor resection. METHODS: The GliaSite is an inflatable balloon catheter that is placed in the resection cavity at the time of tumor debulking. Low-dose-rate radiation is delivered with an aqueous solution of organically bound iodine-125 (lotrex [sodium 3-(125I)-iodo-4-hydroxybenzenesulfonate]), which are temporarily introduced into the balloon portion of the device via a subcutaneous port. Adults with recurrent malignant glioma underwent resection and GliaSite implantation. One to 2 weeks later, the device was filled with Iotrex for 3 to 6 days, following which the device was explanted. Twenty-one patients with recurrent high-grade astrocytomas were enrolled in the study and received radiation therapy. There were two end points: 1) successful implantation and delivery of brachytherapy; and 2) safety of the device. Implantation of the device, delivery of radiation, and the explantation procedure were well tolerated. At least 40 to 60 Gy was delivered to all tissues within the target volume. There were no serious adverse device-related events during brachytherapy. One patient had a pseudomeningocele, one patient had a wound infection, and three patients had meningitis (one bacterial, one chemical, and one aseptic). No symptomatic radiation necrosis was identified during 21.8 patient-years of follow up. The median survival of previously treated patients was 12.7 months (95% confidence interval 6.9-15.3 months). CONCLUSIONS: The GliaSite RTS performs safely and efficiently. It delivers a readily quantifiable dose of radiation to tissue at the highest risk for tumor recurrence.

Adult↗

PubMed2002

Toxicity of intracranial and intraperitoneal O6-benzyl guanine in combination with BCNU delivered locally in a mouse model.

PURPOSE: The DNA-repair protein, O6-alkylguanine-DNA alkyl transferase, may account for resistance of CNS tumors to DNA-alkylating drugs, such as bis-(2-chloroethyl)-1-nitrosourea (BCNU). The therapeutic effects of BCNU can be potentiated by inhibiting the repair protein with an alkylated guanine analog, O6-benzyl guanine (O6BG). To investigate potential toxicity of this inhibition, we examined the effects of O6BG in mice treated with intracranial (i.c.) BCNU given via a biodegradable polymer. METHODS: Mice were treated with escalating doses of BCNU chronically delivered i.c., and with chronically delivered O6BG. The O6BG was delivered via a 7-day intraperitoneal (i.p.) or i.c. osmotic minipump. Toxicity of the combination therapies was measured from survival data. Bone marrow response was estimated from white blood cell counts. RESULTS: Combining systemic (i.p.) O6BG with locally (i.c.) delivered BCNU resulted in a decrease in the maximum tolerated dose (MTD) of local BCNU. With local delivery of O6BG, the MTD of BCNU in combination with O6BG was increased. CONCLUSIONS: Based on the results of this study, a dose escalation study will be necessary when combining systemic O6BG with the higher doses of i.c. BCNU.

Animals↗

PubMed2002

Polymer delivery of camptothecin against 9L gliosarcoma: release, distribution, and efficacy.

Camptothecin is a potent antineoplastic agent that has shown efficacy against multiple tumor lines in vitro; unfortunately, systemic toxicity has limited its in vivo efficacy. This is the first study to investigate the release, biodistribution, and efficacy of camptothecin from a biodegradable polyanhydride polymer. Tritiated camptothecin was incorporated into biodegradable polymers that were implanted intracranially in 16 male Fischer 344 rats and the animals were followed up to 21 days post-implant. A concentration of 11-45 microg of camptothecin-sodium/mg brain tissue was within a 3 mm radius of the polymer disc, with levels of 0.1 microg at the outermost margin of the rat brain, 7 mm from the site of implantation. These tissue concentrations are within the therapeutic ranges for human and rat glioma lines tested against camptothecin-sodium in vitro. The in vivo efficacy of camptothecin-sodium was evaluated with male Fischer 344 rats implanted intracranially with 9L gliosarcoma and compared with the efficacy of 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU). The animals were divided into four groups. Group 1 (control) had a median survival of 17 days. Group 2 (3.8% BCNU polymer) had a median survival of 23 days (P = 0.006). Group 3 (20% camptothecin polymer) had a median survival of 25 days (P = 0.023). Group 4 (50% camptothecin polymer) had a median survival of 69 days (P < 0.001). Drug loadings of 20% and 50% camptothecin released intact camptothecin for up to 1000 h in vitro. We conclude that the biodegradable polymer p(CPP: SA) releases camptothecin-sodium, produces tumoricidal tissue levels, results in little or no systemic toxicity, and prolongs survival in a rat glioma model.

Animals↗

PubMed2002

Multicentric parenchymal xanthogranuloma in a child: case report and review of the literature.

OBJECTIVE AND IMPORTANCE: Xanthogranulomas of the central nervous system are rare, and asymptomatic lesions are often identified in autopsies. We report the first case of a multicentric, cystic, intraparenchymal xanthogranuloma, involving both the supra- and infratentorial compartments, in a 16-month-old girl. CLINICAL PRESENTATION: The clinical presentation consisted of a focal motor seizure in an otherwise healthy infant. INTERVENTION: Gross total removal of the infratentorial lesion was accomplished via a midline suboccipital craniotomy. CONCLUSION: Intracranial xanthogranulomas are rare, and limited experience with the diagnosis of these lesions has been reported. Although most cases are asymptomatic, this case involves a symptomatic, multicentric, intraparenchymal xanthoma in a pediatric patient. Our review of the literature provides further insights regarding the clinical, radiological, and pathological behavior of these lesions and examines the available treatment strategies.

Craniotomy↗