A phase II study of bevacizumab and erlotinib after radiation and temozolomide in MGMT unmethylated GBM patients.

Survival for glioblastoma (GBM) patients with an unmethyated MGMT promoter in their tumor is generally worse than methylated MGMT tumors, as temozolomide (TMZ) response is limited. How to better treat patients with unmethylated MGMT is unknown. We performed a trial combining erlotinib and bevacizumab in unmethylated GBM patients after completion of radiation (RT) and TMZ. GBM patients with an unmethylated MGMT promoter were trial eligible. Patient received standard RT (60 Gy) and TMZ (75 mg/m2 × 6 weeks) after surgical resection of their tumor. After completion of RT they started erlotinib 150 mg daily and bevacizumab 10 mg/kg every 2 weeks until progression. Imaging evaluations occurred every 8 weeks. The primary endpoint was overall survival. Of the 48 unmethylated patients enrolled, 46 were evaluable (29 men and 17 women); median age was 55.5 years (29-75) and median KPS was 90 (70-100). All patients completed RT with TMZ. The median number of cycles (1 cycle was 4 weeks) was 8 (2-47). Forty-one patients either progressed or died with a median progression free survival of 9.2 months. At a follow up of 33 months the median overall survival was 13.2 months. There were no unexpected toxicities and most observed toxicities were categorized as CTC grade 1 or 2. The combination of erlotinib and bevacizumab is tolerable but did not meet our primary endpoint of increasing survival. Importantly, more trials are needed to find better therapies for GBM patients with an unmethylated MGMT promoter.

Phase I study of panobinostat in combination with bevacizumab for recurrent high-grade glioma.

Bevacizumab is frequently used to treat patients with recurrent high-grade glioma (HGG), but responses are generally not durable. Panobinostat is a histone deacetylase inhibitor with anti-neoplastic and anti-angiogenic effects and may work synergistically with VEGF inhibitors. We performed a phase I study to evaluate the safety and tolerability of the combination of orally administered panobinostat with bevacizumab in patients with recurrent HGG. Patients with recurrent HGG were treated on a 3 + 3 trial design. Patients received bevacizumab 10 mg/kg every other week in combination with oral panobinostat. The starting dose of panobinostat was 20 mg three times per week, weekly (cohort 1). Due to concerns for thrombocytopenia with the weekly dosing regimen, the protocol was amended to examine an every other week regimen. Cohort 2 received panobinostat 20 mg three times per week, every other week, and cohort 3 received 30 mg three times per week, every other week. Dose-limiting toxicity during the first 30 days was used to determine the maximum-tolerated dose. Twelve patients (median age 50, median KPS 90) with recurrent HGG were enrolled. One dose-limiting toxicity (DLT) (Grade 3 thrombocytopenia) was observed in cohort 1. No DLTs were observed in cohorts 2 and 3. The following grade 3 toxicities were seen in one patient each: thrombocytopenia, hypophosphatemia, esophageal hemorrhage, and deep venous thrombosis. There were no grade 4 or 5 toxicities. There were three patients with partial responses and seven with stable disease. The recommended doses for further study are oral panobinostat 30 mg three times per week, every other week, in combination with bevacizumab 10 mg/kg every other week. A phase II clinical trial in recurrent HGG is underway.

Multicentre phase II studies evaluating imatinib plus hydroxyurea in patients with progressive glioblastoma.

BACKGROUND: We evaluated the efficacy of imatinib mesylate in addition to hydroxyurea in patients with recurrent glioblastoma (GBM) who were either on or not on enzyme-inducing anti-epileptic drugs (EIAEDs). METHODS: A total of 231 patients with GBM at first recurrence from 21 institutions in 10 countries were enrolled. All patients received 500 mg of hydroxyurea twice a day. Imatinib was administered at 600 mg per day for patients not on EIAEDs and at 500 mg twice a day if on EIAEDs. The primary end point was radiographic response rate and secondary end points were safety, progression-free survival at 6 months (PFS-6), and overall survival (OS). RESULTS: The radiographic response rate after centralised review was 3.4%. Progression-free survival at 6 months and median OS were 10.6% and 26.0 weeks, respectively. Outcome did not appear to differ based on EIAED status. The most common grade 3 or greater adverse events were fatigue (7%), neutropaenia (7%), and thrombocytopaenia (7%). CONCLUSIONS: Imatinib in addition to hydroxyurea was well tolerated among patients with recurrent GBM but did not show clinically meaningful anti-tumour activity.

Phase I trial of bortezomib and carboplatin in recurrent ovarian or primary peritoneal cancer.

PURPOSE: To determine the maximum-tolerated dose, pharmacodynamics, and safety of the combination of bortezomib and carboplatin in recurrent ovarian cancer. PATIENTS AND METHODS: Fifteen patients were treated with a fixed dose of carboplatin (area under the curve [AUC] 5) and increasing doses of bortezomib (0.75, 1, 1.3, and 1.5 mg/m2/dose). Patients must have received upfront chemotherapy and up to two prior chemotherapy regimens for recurrent disease. Neurologic evaluation was performed at baseline and after every two cycles by the Functional Assessment of Cancer Therapy/Gynecologic Oncology Group neurotoxicity questionnaire and examination by an attending neurologist. All patients received carboplatin alone in cycle 1 to establish baseline pharmacodynamics for nuclear factor-kappa B (NF-kB). Starting with cycle 2, patients were treated with carboplatin on day 1 and bortezomib on days 1, 4, 8, and 11. RESULTS: Diarrhea, rash, neuropathy, and constipation (with colonic wall thickening on computed tomography) were dose-limiting toxicities, occurring in the two patients treated at the 1.5 mg/m2/dose level. The Functional Assessment of Cancer Therapy/Gynecologic Oncology Group neurotoxicity questionnaire was helpful in guiding the need for dose reductions. Neurotoxicity was manageable through six cycles, with appropriate dose reductions. Carboplatin had no effect on bortezomib pharmacodynamics as measured by percent inhibition of the 20S proteasome. Bortezomib decreased carboplatin-induced NF-kB. The overall response rate to this combination was 47%, with two complete responses (CR) and five partial responses, including one CR in a patient with platinum-resistant disease. CONCLUSION: The recommended phase II dose of bortezomib administered in combination with carboplatin (AUC 5) is 1.3 mg/m2/dose.

Cerebral sinus thrombosis diagnosed by MRI and MR venography in cancer patients.

OBJECTIVE: To report the characteristics of cerebral sinus thrombosis (CST) in cancer patients diagnosed by MRI and MR venography (MRV). BACKGROUND: CST is a complication of cancer with multiple etiologies and variable symptoms at presentation. Most reports in cancer patients were before the use of MRI and MRV, which has simplified the diagnosis of CST. METHODS: The neurology database at Memorial Sloan-Kettering Cancer Center was used to identify cancer patients with a diagnosis of CST between January 1994 and April 1998. RESULTS: Twenty patients were identified. Nine had hematologic malignancies (HMs) and 11 had solid tumors (STs). The median interval from cancer diagnosis to presentation was 4 months for HMs and 20 months for STs. The most common symptom was headache. MRI and MRV correlated in all but three patients, and MRV was more sensitive in four patients. The most frequently involved cerebral sinus was the superior sagittal sinus. Multiple sinuses were affected in 8 of 19 patients. Five patients had a cerebral or subarachnoid hemorrhage and three had infarction. Disorders of coagulation were the most frequent etiology in patients with HM; compression or invasion of the cerebral sinus from dural/calvarial metastasis was the main cause in those with ST. Treatment was directed at the underlying cause. Ten of 20 patients improved clinically and 3 of 6 patients improved radiologically. CONCLUSION: MRI and MRV can diagnose CST accurately in cancer patients. Causes of CST depend on cancer type, and treatment varies with etiology. Most patients have a good outcome.

Primary intracranial neoplasms in patients with HIV.

OBJECTIVE: To report a series of HIV-infected patients with intracranial tumors not known to be associated with immunodeficiency. BACKGROUND: The spectrum of HIV-associated diseases is changing with improved treatments and prolonged patient survival. Although primary central nervous system lymphoma (PCNSL) and toxoplasmosis continue to be the most common intracranial lesions in HIV-infected patients, the recognition of other pathologic entities is increasingly important. METHODS: The clinical characteristics and outcome of eight HIV-infected patients with nine intracranial neoplasms other than PCNSL are reported. In addition, all available pathologic specimens were tested for evidence of either HIV or Epstein-Barr virus (EBV) infection. An additional 28 patients reported in the literature are summarized. RESULTS: Five of eight patients had a glioblastoma multiforme; other tumors included an anaplastic ependymoma, a low-grade glioma, a subependymoma, and a leiomyosarcoma. More than half of the patients developed their tumor > or =6 years after the diagnosis of HIV infection. Patient prognosis and survival was best predicted by tumor histology. Treatment response and outcome did not appear to be influenced by HIV infection. Only the leiomyosarcoma demonstrated evidence of latent EBV infection. CONCLUSIONS: HIV-infected patients are at risk for intracranial neoplasms other than PCNSL, and benefit from aggressive tumor-specific therapy. It is possible that gliomas are occurring at a higher rate than in the general population. There was no evidence of HIV or EBV infection in any glial tumor.

Conditioned taste aversions are not readily disrupted by external excitation.

Thirsty male rats were given saccharin water followed by delayed illness. During the delay, some of the rats were exposed to events designed to stimulate their external systems (i.e., the system that processes external events such as auditory and tactile stimulation). Access to females, mild footshocks, and pain from hypertonic saline injections did not interfere with either the acquisition or extinction of a taste aversion. In fact, when administered intraperitoneally, the hypertonic saline slightly increased the strength of the aversion. Exposure to heat, which changed both skin temperature and core temperature, slightly attenuated the formation of the aversion. Overall, these results emphasize the independence of the internal system (i.e., the system that deals with internal events such as taste, illness, and core temperature) and the external system. Furthermore, the associating of events related to the internal system is not readily interfered with by events related to the external system.

Stressors in the learned helplessness paradigm: effects on body weight and conditioned taste aversion in rats.

Changes in body weight and taste aversion in the learned helplessness paradigm were examined. In Experiment 1, adult male Sprague-Dawley rats drank saccharin or a control solution, followed by either 100 inescapable shocks or simple restraint. Rats were weighted daily and were tested for saccharin aversion two days after the stress session. Shocked rats gained less weight in the days after stress than restrained controls. Saccharin aversion was apparent only among rats that had consumed saccharin before the stress session. Experiment 2 examined whether control over shock affected body weight or taste aversion. Home-cage controls were included to assess the effects of restraint alone. In addition, the combined effects of shock and a toxin on aversion were studied. Rats drank saccharin solution, followed by escapable or inescapable shock, restraint, or no treatment. Then half of each group was injected with saline; the other half was injected with lithium chloride. As in Experiment 1, shock reduced body weight relative to restraint or no treatment, and shock produced a taste aversion among saline-treated rats. However, shock attenuated the aversion produced by lithium chloride, as did simple restraint. There were no differences in body weight or taste aversion between escapably and inescapably shocked rats. These results suggest a role for stress in the anorexia and weight loss associated with clinical depression and may have implications for theories of learning and learned helplessness.

Single-stage posterolateral transpedicle approach for spondylectomy, epidural decompression, and circumferential fusion of spinal metastases.

STUDY DESIGN: Retrospective review of prospectively maintained institutional spine database. OBJECTIVES: To assess the pain, neurologic, and functional outcome of patients with metastatic spinal cord compression using a posterolateral transpedicular approach with circumferential fusion. SUMMARY OF BACKGROUND DATA: Patients with spinal metastases often have patterns of disease requiring both an anterior and posterior surgical decompression and spinal fusion. For patients whose concurrent illness or previous surgery makes an anterior approach difficult, a posterior transpedicular approach was used to resect the involved vertebral bodies, posterior elements, and epidural tumor. This approach provides exposure sufficient to decompress and instrument the anterior and posterior columns. METHODS: During the past 15 months, 25 patients were operated on using a posterolateral transpedicular approach. The primary indications for surgery were back pain (15 patients) and neurologic progression (10 patients). All patients had vertebral body disease, and 21 patients had high-grade spinal cord compression from epidural disease as assessed by magnetic resonance imaging. Seven patients underwent preoperative embolization for vascular tumors. In each patient, the anterior column was reconstructed with polymethyl methacrylate and Steinmann pins and the posterior column with long segmental fixation. RESULTS: All patients achieved immediate stability. Pain relief was significant in all 23 patients who had had moderate or severe pain. Neurologic symptoms were stable or improved in 23 patients. One patient with an acutely evolving myelopathy was immediately worse after surgery, and one patient had a delayed neurologic worsening, progressing to paraplegia. CONCLUSIONS: The posterolateral transpedicular approach provides a wide surgical exposure to decompress and instrument the anterior and posterior spine. This technique avoids the morbidity associated with anterior approaches and provides immediate stability. Vascular tumors may be removed safely after embolization. Patients can be mobilized early after surgery.

Water uptake, priming, drying and storage effects in Cassia excelsa Schrad seeds.

The aims of this study were to evaluate the effects of osmotic potential on the water uptake curve in Cassia excelsa seeds and use the results to analyze the effects of dehydration and storage on primed seed germination. Seeds were imbibed in distilled water and polyethylene glicol (PEG 6000) osmotic solutions at -0.2, -0.4, and -0.6 MPa, at 20 degrees C. The radicle emergence and seed moisture content were evaluated at 6-hour intervals during 240 hours. Afterwards, seeds were primed in distilled water and PEG 6000 solutions at -0.2, -0.4, and -0.6 MPa for 48, 72, 96, and 168 hours at 20 degrees C, followed by air drying and storage for 15 days at 5 degrees C. The lower the osmotic potential, the higher the time required for priming. The osmoconditioning yields benefits with PEG solutions at 0.0 and -0.2 MPa; seed improvements were maintained during storage for 15 days at 5 degrees C, but were reverted by seed drying.

Chemotherapy: What is its role in meningioma?

While strong evidence exists for the standard therapy for meningiomas, inclusive of surgery and/or radiation therapy, for those tumors which recur, progress or are inoperable, the optimal medical therapies are yet to be elucidated. This article reviews the current literature for chemotherapeutic options for this subset of tumors, including cytotoxic agents, biologic agents, targeted molecular agents and hormonal agents. At this point in time, the most data is with hydroxyurea and somatostatin, although further trials with combination and targeted molecular therapies are still underway.

Primary CNS lymphoma with intraocular involvement: International PCNSL Collaborative Group Report.

OBJECTIVE: To describe the demographics, diagnostic details, therapeutic management, and outcome in patients with primary CNS lymphoma (PCNSL) with ocular involvement. METHODS: A retrospective study of 221 patients was assembled from 16 centers in seven countries. Only HIV-negative, immunocompetent patients with brain and ocular lymphoma were included; none had systemic lymphoma. RESULTS: Median age at diagnosis was 60. Fifty-seven percent were women. Median Eastern Cooperative Oncology Group performance status was 2. Ocular disturbance and behavioral/cognitive changes were the most common presenting symptoms. Diagnosis of lymphoma was made by brain biopsy (147), vitrectomy (65), or CSF cytology (11). Diagnosis of intraocular lymphoma was made by vitrectomy/choroidal/retinal biopsy (90) or clinical ophthalmic examination (141). CSF cytology was positive in 23%. Treatment information was available for 176 patients. A total of 102 received dedicated ocular therapy (ocular radiotherapy 79, intravitreal methotrexate 22, and both 1) in addition to treatment for their brain lymphoma. Sixty-nine percent progressed at a median of 13 months; sites of progression included brain 52%, eyes 19%, brain and eyes 12%, and systemic 2%. Patients treated with local ocular therapy did not have a statistically significant decreased risk of failing in the eyes (p = 0.7). Median progression free survival and overall survival for the entire cohort were 18 and 31 months. CONCLUSION: This is the largest reported series of primary CNS lymphoma (PCNSL) with intraocular involvement. Progression free and overall survival was similar to that reported with PCNSL. Dedicated ocular therapy improved disease control but did not affect overall survival.

Vinorelbine combined with a protracted course of temozolomide for recurrent brain metastases: a phase I trial.

Temozolomide (TMZ) has shown modest efficacy in the treatment of recurrent brain metastasis (BM). We designed a new regimen utilizing dose-intensified, protracted course of TMZ in combination with vinorelbine, a lipophilic large-spectrum agent, in an attempt to improve the efficacy of TMZ. This phase I study was conducted to establish the maximum tolerated dose (MTD) of vinorelbine for this combination. Patients with recurrent or progressive BM were eligible. Chemotherapy consisted of 28-day cycles with TMZ (150 mg/m2, days 1-7 and 15-21) and vinorelbine (days one and eight at escalating doses). The starting dose was 15 mg/m2, with increments of 5 mg/m2 for each cohort of 3-6 patients, until MTD was reached (30 mg/m2). A total of 21 patients were enrolled; the median age was 59 (41-77). The primary tumor was lung cancer in 13 patients (NSCLC in 10, SCLC in 3), breast in 6, renal in 1 and endometrial in 1. Vinorelbine dose was 15 mg/m2 in seven patients, 20 mg/m2 in five, 25 mg/m2 in four and 30 mg/m2 in six. Grades 3 and 4 neutropenia developed in six patients, lymphopenia in nine, and thrombocytopenia in six; other toxicities were rare. No dose-limiting toxicity was seen. Out of 18 evaluable patients 2 had a radiographic response (one partial and one minor). Disease was stable in 6 of 18 patients and the median survival was 27 weeks. This regimen was well tolerated and a phase II trial using a dose of 30 mg/m2 of vinorelbine is warranted.

Capecitabine-induced multifocal leukoencephalopathy: a report of five cases.

Capecitabine is used to treat advanced breast and gastrointestinal malignancies. A single case of encephalopathy and three cases of peripheral neuropathy are the only neurotoxicities reported. The authors report five additional cases of capecitabine-induced multifocal leukoencephalopathy.

Proton magnetic resonance spectroscopy in immunocompetent patients with primary central nervous system lymphoma.

BACKGROUND: Magnetic resonance spectroscopy imaging (MRSI) non-invasively evaluates the metabolic profile of normal and abnormal brain tissue. Primary central nervous system lymphoma (PCNSL) is a highly aggressive tumor responsive to high-dose methotrexate based regimens. Patients often have complete responses but relapses are common. We characterized the MR spectra of PCNSL patients, correlated MRSI with MRI and evaluated whether early recurrence could be detected by MRSI. METHODS: Patients with PCNSL had multi-voxel MRSI before, during, and after treatment. The region of interest was defined using axial FLAIR images. Metabolites assessed were N-acetyl-aspartate (NAA), choline (Cho), creatine (Cr), lipid, and lactate. Ratios of Cho/Cr, NAA/Cho, and NAA/Cr were calculated and correlated with MRI. Overall survival (OS), progression free survival (PFS), and relative risks of each of the ratios were determined. RESULTS: MRSI was performed on 11 men and seven women; median age of 59. Sixty-seven MRSI studies were performed, 17 baseline and 48 follow-up studies. Median ratios in 16 pretreated patients were Cho/Cr-1.90, NAA/Cho-0.39, and NAA/Cr-1.27. Two patients had lipid at baseline, five had lactate and two had both. MRSI correlated with tumor response or progression on MRI; in three patients MRSI suggested disease progression prior to changes on MRI. Univariate analysis of metabolite ratios, lipid, and lactate revealed that none significantly affected PFS or OS. Kaplan-Meier analysis of the presence or absence of lipid, lactate or both revealed a trend for increased PFS. CONCLUSION: MRSI and MRI correlate with tumor response or progression and may allow early detection of disease recurrence. The presence or absence of lipid and/or lactate may have prognostic significance. Further research using MRSI needs to be done to validate our findings and determine the role of MRSI in PCNSL.

The diagnosis and treatment of metastatic spinal tumor.

Metastases to the spine represent a challenging problem in an oncology practice. Treatment decisions require multidisciplinary review. Radiation therapy remains the primary treatment for metastatic spinal tumor, but advances in radiation therapy, chemotherapy, and surgery have changed the roles of each and lead to improved patient outcomes. Regardless of the treatment, diagnosis and treatment before the development of significant neurologic and functional deficits improve outcomes. Physician awareness and appropriate imaging greatly assist in the early detection of tumor.

A phase II trial of temozolomide for patients with recurrent or progressive brain metastases.

BACKGROUND: Treatment options for patients with recurrent brain metastases are extremely limited. This study was designed to determine the safety and efficacy of temozolomide in the treatment of recurrent or progressive brain metastases. PATIENTS AND METHODS: Forty-one patients (11 men, 30 women) with a median KPS of 80 were treated with temozolomide 150 mg/m2/day (200 mg/m3/day if no prior chemotherapy) for 5 days; treatment cycles were repeated every 28 days. Primary tumor types included 22 non-small cell lung, 10 breast, three melanoma, two small cell lung, two rectal, one ovarian and one endometrial cancer. RESULTS: There were five episodes of grade 3 thrombocytopenia and one grade 4 leukopenia. Significant non-hematologic toxicity possibly related to temozolomide included pneumonitis [21, constipation [1], and elevated liver enzymes [21. Thirty-four patients were assessed for radiographic response; two had a partial response, 15 stable disease and 17 progressed. Both objective responses were seen in patients with non-small cell lung cancer. Overall median survival was 6.6 months. CONCLUSIONS: Single agent temozolomide achieved disease control (PR or SD) in 41% of patients with recurrent brain metastases from a variety of primary malignancies with minimal toxicity. Therefore, temozolomide may be a reasonable treatment option for some patients with recurrent brain metastases.

Water uptake, priming, drying and storage effects inCassia excelsa Schrad seeds

The aims of this study were to evaluate the effects of osmotic potential on the water uptake curvein Cassia excelsa seeds and use the results to analyze the effects of dehydration and storage on primed seed germination. Seeds were imbibed in distillad water and polyethylene glicol (PEG 6000) osmotic solutions at -0.2, -0.4, and -0.6 MPa, at 20C. The radicle emergence and seed moisture content were evaluated at 6-hour intervals during 240 hours. Afterwards, seeds were primed in distillad water and PEG 6000 solutions at -0.2, -0.4, and -0.6 MPa for 48, 72, 96, and 168 hours at 20C, followed by air drying and storage for 15 days at 5C. The lower the osmotic potential, the higher the time required for priming. The osmoconditioning yields benefits with PEG solutions at 0.0 and -0.2 MPa; seed improvements were maintained during storage for 15 days at 5C, but were reverted by seed drying