Camilo E. Fadul

Recurrent meningioma: salvage therapy with long-acting somatostatin analogue.

Background: Somatostatin receptors, especially the sst2A subtype, are present on most meningiomas. The addition of somatostatin inhibits meningioma growth in vitro in some studies. There have been anecdotal reports of octreotide inhibiting growth in meningiomas. Objectives: A prospective pilot trial of sustained-release somatostatin (Sandostatin LAR) in 16 patients with recurrent meningiomas was conducted with a primary study objective of progression-free survival at 6 months. Methods: Sixteen patients (11 women, 5 men; median age 58) with recurrent meningioma were treated prospectively with long-acting somatostatin. Patients had progressed radiographically after prior therapy with surgery (14/16; complete resection in 5; subtotal in 7; biopsy only in 2), radiotherapy (13/16), and chemotherapy (12/16). All patients had confirmation of the presence of somatostatin receptors in their tumor using 111In-octreotide, a long-acting somatostatin agonist, SPECT scanning. Results: Patients received 2 to 15 cycles (median 4.5) of somatostatin with minimal toxicity. Four partial responses, five stable disease, and seven progressive disease patterns were seen. Duration of response ranged from 2 to 20+ months (median 5.0 months). Median survival was 7.5 months (range 3 to 20+). The overall progression-free survival was 44% (seven patients) at 6 months. Conclusions: In this small trial of patients with recurrent meningiomas shown to overexpress somatostatin receptors by octreotide scintigraphy, long-acting somatostatin (Sandostatin LAR) was administered on a monthly schedule. Thirty-one percent of patients demonstrated a partial radiographic response and 44% achieved progression-free survival at 6 months. Toxicity was minimal, suggesting somatostatin analogues may offer a novel, relatively nontoxic alternative treatment for recurrent meningiomas.

Immune response in patients with newly diagnosed glioblastoma multiforme treated with intranodal autologous tumor lysate-dendritic cell vaccination after radiation chemotherapy.

Patients with glioblastoma multiforme (GBM) are profoundly immunosuppressed and may benefit from restoration of an antitumor immune response in combination with conventional radiation therapy and temozolomide (TMZ). The optimal strategies to evaluate clinically relevant immune responses to treatment have yet to be determined. The primary objective of our study was to determine immunologic response to cervical intranodal vaccination with autologous tumor lysate-loaded dendritic cells (DCs) in patients with GBM after radiation therapy and TMZ. We used a novel hierarchical clustering analysis of immune parameters measured before and after vaccination. Secondary objectives were to assess treatment feasibility and to correlate immune response with progression-free survival (PFS) and overall survival. Ten eligible patients received vaccination. Tumor-specific cytotoxic T-cell response measured after vaccination was enhanced for the precursor frequency of CD4+ T and CD4+ interferon &ggr;-producing cells. Hierarchical clustering analysis of multiple functional outcomes discerned 2 groups of patients according to their immune response, and additionally showed that patients in the top quintile for at least one immune function parameter had improved survival. There were no serious adverse events related to DC vaccination. All patients were alive at 6 months after diagnosis and the 6-month PFS was 90%. The median PFS was 9.5 months and overall survival was 28 months. In patients with GBM, immune therapy with DC vaccination after radiation and TMZ resulted in tumor-specific immune responses that were associated with prolonged survival. Our data suggest that DC vaccination in combination with radiation and chemotherapy in patients with GBM is feasible, safe, and may induce tumor-specific immune responses.

Brain activation patterns associated with working memory in relapsing-remitting MS.

Background: Patients with multiple sclerosis (MS) show changes in brain activation patterns during visual and motor tasks that include decreases in the typical local network for a function and increases in other brain regions. Objective: To determine whether brain activation patterns associated with working memory are affected by MS. Methods: Activation of working memory circuitry was examined using an fMRI n-back task in adults with mild relapsing-remitting MS (RRMS; n = 10) and demographically matched healthy controls (n = 10). Results: Group differences in brain activation emerged during both low- and high-demand conditions (p < 0.001). Overall, patients showed less activation than controls in core prefrontal and parietal regions of working memory circuitry, and greater activation in other regions within and beyond typical working memory circuitry, including bilateral medial frontal, cingulate, parietal, bilateral middle temporal, and occipital regions. Conclusions: Relative to controls, patients with mild RRMS showed shifts in brain activation patterns within and beyond typical components of working memory circuitry.

Antitumour effects of temozolomide in a man with a large, invasive prolactin‐producing pituitary neoplasm

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Chronic deep brain stimulation for the treatment of tremor in multiple sclerosis: review and case reports

Background: Deep brain stimulation (DBS) offers a non-ablative alternative to thalamotomy for the surgical treatment of medically refractory tremor in multiple sclerosis. However, relatively few outcomes have been reported. Objective: To provide a systematic review of the published cases of DBS use in multiple sclerosis and to present four additional patients. Methods: Quantitative and qualitative review of the published reports and description of a case series from one centre. Results: In the majority of reported cases (n=75), the surgical target for DBS implantation was the ventrointeromedial nucleus of the thalamus. Tremor reduction and improvement in daily functioning were achieved in most patients, with 87.7% experiencing at least some sustained improvement in tremor control postsurgery. Effects on daily functioning were less consistently assessed across studies; in papers reporting relevant data, 76.0% of patients experienced improvement in daily functioning. Adverse effects were similar to those reported for DBS in other patient populations. Conclusions: Few of the studies reviewed used highly standardised quantitative outcome measures, and follow up periods were generally one year or less. Nonetheless, the data suggest that chronic DBS often produces improved tremor control in multiple sclerosis. Complete cessation of tremor is not necessarily achieved, there are cases in which tremor control decreases over time, and frequent reprogramming appears to be necessary.

Perforation of the gastrointestinal tract in patients receiving steroids for neurologic disease

Between 1980 and 1984, of 107 patients receiving 16 mg/d of dexamethasone for spinal cord compression, three (2. 8%) developed gastrointestinal (GI) perforation and two (1.9%) GI bleeding; of 226 being tapered from 100 mg/d of dexamethasone, perforation occurred in six (2.7%) and GI bleeding in eight (3. 5%). Of 125 patients with GI perforations treated between 1979 and 1986, 41 (33%) were on steroids, 24 for neurologic disease. Median duration of steroid therapy was 24 days; 20 (91%) of the neurologic patients perforated within 30 days. The steroid group had more free peritoneal involvement (p < 0. 00001), but fewer signs and symptoms of peritonitis (p < 0. 000001) than the nonsteroid group. Seventeen patients were receiving steroids for cord compression; they had significantly more rectosigmoid perforations (p < 0. 014) and associated constipation (p < 0. 000001) than the 108 remaining patients. GI perforation is a less well-recognized complication of steroid therapy in neurologic patients than is GI bleeding though it occurs as frequently, is more difficult to diagnose, and far more serious. In steroid-treated patients, prevention of constipation might avert this serious complication, while early diagnosis will improve the outcome.

Efficacy of thalidomide for the treatment of amyotrophic lateral sclerosis: A phase II open label clinical trial

Neuroinflammation through the cytokine, tumor necrosis factor-alpha (TNF-α) is thought to play an important role in the pathogenesis of amyotrophic lateral sclerosis (ALS). We conducted a preliminary phase II trial of thalidomide, which reduces levels of TNF-α pre-transcriptionally and post-transcriptionally in vivo and has been shown to prolong disease duration and extend the lifespan of transgenic animal models of ALS. Patients who met diagnostic criteria for ALS received thalidomide at escalating doses to a target dose of 400 mg/day. The primary endpoints in the trial were the ALS Functional Rating Scale (ALSFRS) and pulmonary function testing (PFT) curves after nine months of thalidomide treatment that were compared to historical controls. Secondary endpoints were: survival stratified for newly diagnosed and progressive disease, toxicity, quality of life, and serum cytokine measurements. Twenty-three patients were enrolled, but only 18 were evaluable for the primary outcome. There was no improvement in the ALSFRS or PFT compared to historical controls. Thalidomide had several side-effects in our ALS patients. There was no significant shift in cytokine profile after treatment compared to baseline. In conclusion, treatment of ALS with the TNF-α inhibitor, thalidomide, does not appear to effectively modulate disease progression and can cause adverse effects.

Immune modulation effects of concomitant temozolomide and radiation therapy on peripheral blood mononuclear cells in patients with glioblastoma multiforme

Concomitant radiation therapy (RT) and temozolomide (TMZ) therapy after surgery is the standard treatment for glioblastoma multiforme (GBM). Radiation and chemotherapy can affect the immune system with implications on subsequent immune therapy. Therefore, we examined the phenotype and function of peripheral blood mononuclear cells in 25 patients with GBM prior to and 4 weeks after treatment with RT-TMZ using multicolor flow cytometry, as well as in vitro CD4(+) regulatory T cell (T(reg)) suppressor and dendritic cell maturation assays. RT-TMZ induced significant lymphopenia, with a decrease in total CD4(+) T cells, but did not significantly change monocyte counts. The proportion of functional T(reg) cells increased after treatment, whereas their absolute numbers remained stable. There was also a measurable decrease in the proportion of CD8(+)CD56(+) and absolute number of CD3(-)CD56(+) effector cells. Posttherapy monocytes retained the ability to mature into dendritic cells. Treatment with RT-TMZ is associated with changes in regulatory and effector peripheral blood mononuclear cells that tilt the balance towards an immune suppressive state. This shift can affect the outcome of immune therapy following RT-TMZ treatment and should be considered in the design of future combination therapy regimens.

Phase 2 study of dose-intense temozolomide in recurrent glioblastoma

BACKGROUND Among patients with glioblastoma (GBM) who progress on standard temozolomide, the optimal therapy is unknown. Resistance to temozolomide is partially mediated by O(6)-methylguanine-DNA methyltransferase (MGMT). Because MGMT may be depleted by prolonged temozolomide administration, dose-intense schedules may overcome resistance. METHODS This was a multicenter, phase 2, single-arm study of temozolomide (75-100 mg/m(2)/day) for 21 days of each 28-day cycle. Patients had GBM in first recurrence after standard therapy. The primary end point was 6-month progression-free survival (PFS6). RESULTS Fifty-eight participants were accrued, 3 of whom were ineligible for analysis; one withdrew before response assessment. There were 33 men (61%), with a median age of 57 years (range, 25-79 years) and a median Karnofsky performance score of 90 (range, 60-100). Of 47 patients with MGMT methylation results, 36 (65%) had methylated tumors. There were 7 (13%) partial responses, and PFS6 was only 11%. Response and PFS did not depend on MGMT status; MSH2, MLH1, or ERCC1 expression; the number of prior temozolomide cycles; or the time off temozolomide. Treatment was well tolerated, with limited grade 3 neutropenia (n = 2) or thrombocytopenia (n = 2). CONCLUSIONS Dose-intense temozolomide on this schedule is safe in recurrent GBM. However, efficacy is marginal and predictive biomarkers are needed.

Management of newly diagnosed glioblastoma: guidelines development, value and application

The movement to create guidelines for management of medical maladies has been gaining strength for quality, academic, financial and political purposes over the past two decades. This applies to neurological diseases, too. Evidence-based guidelines created in a multidisciplinary fashion using predetermined criteria for grading scientific data and translating this to similarly ranked recommendations is a valuable approach to meeting this goal. The following is a summary of the methods used for, and the results of, an evidence-based guideline for the management of newly diagnosed glioblastoma. In addition to outlining recommendations by discipline, it also addresses how concerns and conflicts were addressed in their development and provides comment on future directions in management of this situation that may improve outcome. It is important that clinicians directly experienced in patient management take the lead in creation of guidelines related to the diseases they deal with, as these clinicians are clearly the most suited to being able to arrive at a meaningful and useful product.