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This phase II trial evaluated efficacy and safety of temozolomide (TMZ) in combination with irinotecan (CPT-11) before radiotherapy in patients with newly diagnosed glioblastoma multiforme (GBM). Prior to radiotherapy, patients we...
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This phase II trial evaluated efficacy and safety of temozolomide (TMZ) in combination with irinotecan (CPT-11) before radiotherapy in patients with newly diagnosed glioblastoma multiforme (GBM). Prior to radiotherapy, patients were treated with a maximum of three 6-week cycles of TMZ and CPT-11. Patients received TMZ at a dose of 200 mg/m(2)/day on days 1-5 and CPT-11 on days 1, 8, 22, and 29, with a dose adjustment for enzyme-inducing antiepileptic drug use. The primary end point was objective response rate (ORR). Secondary end points included progression-free survival (PFS), overall survival (OS), safety, and tumor O(6)-methylguanine-DNA methyltransferase (MGMT) expression. Of the 42 patients treated, 8 (19%) patients achieved a partial response. Median PFS and median OS were 3.1 and 13.8 months, respectively. Grade 3 or 4 AEs were documented in 36% of patients, most of which were hematologic (29%). Twenty-four percent of patients had grade 3 or 4 non-hematologic AEs, with gastrointestinal AEs being the most common (12%) Two patients died, one of intracranial hemorrhage and one of treatment-related renal failure. Low MGMT expression, compared with high MGMT expression, showed no significant difference in ORR (25 vs. 8%), median PFS (14 vs. 5 months) or OS (21 vs. 15 months). Although TMZ plus CPT-11 is at least comparable in efficacy to TMZ alone, this combination appears more toxic and poorly tolerated. The lack of correlation of activity with MGMT expression is intriguing, but needs further evaluation in subsequent trials.
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Conventional therapies for glioblastoma multiforme (GBM) fail to target tumor cells exclusively, such that their efficacy is ultimately limited by nonspecific toxicity. Immunologic targeting of tumor-specific gene mutations, howev...
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Conventional therapies for glioblastoma multiforme (GBM) fail to target tumor cells exclusively, such that their efficacy is ultimately limited by nonspecific toxicity. Immunologic targeting of tumor-specific gene mutations, however, may allow more precise eradication of neoplastic cells. The epidermal growth factor receptor variant III (EGFRvIII) is a consistent and tumor-specific mutation widely expressed in GBMs and other neoplasms. The safety and immunogenicity of a dendritic cell (DC)-based vaccine targeting the EGFRvIII antigen was evaluated in this study. Adults with newly diagnosed GBM, who had undergone gross-total resection and standard conformal external beam radiotherapy, received three consecutive intradermal vaccinations with autologous mature DCs pulsed with an EGFRvIII-specific peptide conjugated to keyhole limpet hemocyanin. The dose of DCs was escalated in cohorts of three patients. Patients were monitored for toxicity, immune response, radiographic and clinical progression, and death. No allergic reactions or serious adverse events were seen. Adverse events were limited to grade 2 toxicities. The maximum feasible dose of antigen-pulsed mature DCs was reached at 5.7 x 10(7) +/- 2.9 x 10(7) SD without dose-limiting toxicity. EGFRvIII-specific immune responses were evident in most patients. The mean time from histologic diagnosis to vaccination was 3.6 +/- 0.6 SD months. Median time to progression from vaccination was 6.8 months [95% confidence interval (C.I.(95)), 2.5-8.8], and median survival time from vaccination was 18.7 months (C.I.(95), 14.5-25.6). Overall median survival from time of histologic diagnosis was 22.8 months (C.I.(95), 17.5-29). This study establishes the EGFRvIII mutation as a safe and immunogenic tumor-specific target for immunotherapy.
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PURPOSE: The exposure of the third segment of the extracranial vertebral artery (V3) is an important step in the extreme lateral inferior transcondylar-transtubercular exposure (ELITE) approach. The muscular suboccipital triangle ...
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PURPOSE: The exposure of the third segment of the extracranial vertebral artery (V3) is an important step in the extreme lateral inferior transcondylar-transtubercular exposure (ELITE) approach. The muscular suboccipital triangle provides one of the landmarks to identify the V3 segment; however, identification of this triangle and dissection of the V3 segment is not always straightforward in the actual surgery. Blind dissection below the level of the foramen magnum can lead to vertebral artery injury. While the surgeon may be able to readily define the V3 segment of the vertebral artery by feeling its pulse, it is important to have a safe systematic approach to finding the V3 segment when the vessel is illusive. We propose a simple method to identify the V3 segment avoiding accidental injury of the vertebral artery. METHODS: Sixteen cadaver heads (using both sides) were prepared by injecting red- or blue-coloured silicone into their arteries and veins, respectively. We performed an ELITE bilaterally on each cadaver head following four key bony landmarks. A postauricular lazy S-shaped skin incision was made centered just behind the mastoid tip. The posterior neck muscles were cut along the line of the skin incision behind the attachment of the sternocleidomastoid muscle to expose the occipital bone. All the incised muscles were reflected anteriorly as the ELITE is a dorsolateral approach. A suboccipital craniotomy was made exposing the posterior half of the sigmoid sinus up to the inferior retrosigmoid point (point A). The foramen magnum was opened after the craniotomy was completed. The dura on the foramen magnum was followed posteriorly in order to identify the occipital midline dural point (point B) that is identified by the bony ridge at the junction of the posterior fossa dura on the foramen magnum and the posterior most aspect of the spinal dura. The posterior tubercle of C1 (point C) was identified directly inferior to Point B. The posterior arch of C1 was followed anteriorly from the tubercle to find the "J-groove", which cradles the vertebral artery (point D). The V3 segment lies above this groove, covering the paravertebral venous plexus. We measured the distances between the landmarks introduced above after completion of the exposure. RESULTS: The distance between points A and B was 30.5 +/- 5.6 mm, points B-C was 10.4 +/- 2.3 mm, points C-D was 19.1 +/- 3.8 mm. The V3 segment was identified using the anatomical relationships described above in all heads. In no cadaver specimen was the artery injured. CONCLUSIONS: Identification of the V3 segment of the vertebral artery by systematically detecting the four anatomical points defined above is simple and much safer than a direct dissection below the foramen magnum.
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