Faculty Bibliography

Background/UNASSIGNED:Primary extranodal marginal zone lymphoma (MZL) of the dura is a rare neoplastic entity in the central nervous system (CNS). Methods/UNASSIGNED:We used literature searches to identify previously reported cases of primary dural MZL. We also reviewed clinical, pathologic, and radiographic data of an adult patient with concurrent dural MZL and chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL). Results/UNASSIGNED:We identified 104 cases of dural MZL in the literature. None of them presented concurrently with another type of non-Hodgkin lymphoma. This is the first report of composite lymphoma consisting of dural MZL and CLL/SLL in the bone marrow and lymph nodes. Conclusion/UNASSIGNED:Primary dural MZL is a rare, indolent low-grade CNS lymphoma, with a relatively good prognosis. Its treatment is multidisciplinary and often requires surgical intervention due to brain compression, along with low to moderate doses of radiotherapy and/or systemic chemotherapy.

Background: Invasion is a dominant escape mechanism following angiogenic blockade in glioblastomas (GBM). Lithium has shown anti-invasive activity in glioma cells by inhibiting Glycogen Synthetase Kinase -3. This phase II study evaluated the safety and efficacy of using lithium and bevacizumab (BEV) in newly diagnosed GBM. Methods: From 2010 through 2012, 20 GBM patients with residual disease after surgery were treated with involved-field radiation therapy to 5940 cGy and concomitant temozolomide (TMZ) (75 mg/m2 daily for 42 days) along with BEV (10 mg/kg every 2 weeks), starting 29 days after surgery. This was followed by six 28-day cycles of TMZ (150 mg/m2 on days 1-7, BEV (10 mg/kg) on days 8 and 22, and lithium 300 mg BID. Lithium was increased every 7 days up to 600 mg BID with a serum lithium goal level of 0.8 to 1.2 mEq/L. Results: The median follow-up was 9.9 months (range 1.9-24.5). Fourteen patients (70.0%) received at least one dose of lithium and three patients completed the entire course of therapy. The median number of BEV infusion was 9 (range 2-19). Five patients discontinued trial due to skin sensitivity (n = 2), pulmonary embolism (n = 1), infection (n = 1), and hematological toxicity (n=1). Two patients experienced dose limiting lithium toxicity which included drowsiness (n = 1) and tremor (n = 1). No patients experienced grade 3/4 intra-cranial hemorrhage. The median progression free survival (PFS) was 9.3 months. The 12-month PFS and OS were 31.9% and 59.3% respectively. For the 14 patients who received lithium, the 12-month PFS and OS were 42.9% and 69.2% respectively. Conclusions: The strategy of targeting angiogenesis and invasion simultaneously in newly diagnosed GBM is effective and feasible

Object The presence of angiogenesis is a hallmark of glioblastoma (GBM). Vascular endothelial growth factor (VEGF), which drives angiogenesis, provides an additional target for conventional therapy. The authors conducted a prospective clinical trial to test the effectiveness of bevacizumab, an inhibitor of VEGF, in newly diagnosed GBM. Methods From 2006 through 2010, 51 eligible patients with newly diagnosed GBM were treated with involved-field radiation therapy and concomitant temozolomide (75 mg/m(2) daily for 42 days) along with bevacizumab (10 mg/kg every 2 weeks), starting 29 days after surgery. This was followed by 6 cycles of adjuvant temozolomide therapy (150 mg/m(2) on Days 1-7 of a 28-day cycle) with bevacizumab administered at 10 mg/kg on Days 8 and 22 of each 28-day cycle. Results The 6- and 12-month progression-free survival (PFS) rates were 85.1% and 51%, respectively. The 12- and 24-month overall survival (OS) rates were 85.1% and 42.5%, respectively. Grade III/IV toxicities were noted in 10 patients (19.6%). No treatment-related deaths were observed. Asymptomatic intracranial bleeding was noted in 5 patients. Conclusions The addition of bevacizumab to conventional therapy in newly diagnosed GBM appears to improve both PFS and OS in patients with newly diagnosed GBM, with acceptable morbidity. A shift toward diffuse relapse was noted in a significant number of patients. Ongoing Phase III clinical trials will show the true benefit of this antiangiogenic approach.

PURPOSE: Local recurrence is the dominant pattern of relapse in high-grade glioma (HGG) after conventional therapy. The recent use of antiangiogenic therapy has shown impressive radiologic and clinical responses in adult HGG. The preclinical data suggesting increased invasiveness after angiogenic blockade have necessitated a detailed analysis of the pattern of recurrence after therapy. METHODS AND MATERIALS: A total of 162 consecutive patients with HGG, either newly diagnosed (n = 58) or with recurrent disease (n = 104) underwent therapy with bevacizumab at 10 mg/kg every 2 weeks and conventional chemotherapy with or without involved field radiotherapy until disease progression. The pattern of recurrence and interval to progression were the primary aims of the present study. Diffuse invasive recurrence (DIR) was defined as the involvement of multiple lobes with or without crossing the midline. RESULTS: At a median follow-up of 7 months (range, 1-37), 105 patients had recurrence, and 79 patients ultimately developed DIR. The interval to progression was similar in the DIR and local recurrence groups (6.5 and 6.3 months, p = .296). The hazard risk of DIR increased exponentially with time and was similar in those with newly diagnosed and recurrent HGG (R(2) = 0.957). The duration of bevacizumab therapy increased the interval to recurrence (p < .0001) and improved overall survival (p < .0001). However, the pattern of relapse did not affect overall survival (p = .253). CONCLUSION: Along with an increase in median progression-free survival, bevacizumab therapy increased the risk of DIR in HGG patients. The risk of increased invasion with prolonged angiogenic blockade should be addressed in future clinical trials

Purpose: The role of invasion as a prognostic factor in high-grade gliomas (HGG) remains controversial. An apparent increase in invasiveness following anti-angiogenic therapy makes this question clinically relevant. The goal of this study is to assess survival differences in patients with newly diagnosed HGG who present with diffuse invasive disease compared to those who did not, but went on to develop diffuse invasive disease following bevacizumab therapy. Materials and Methods: Twenty-three patients presented as newly diagnosed diffuse invasive HGG. All patients underwent surgical resection with radiation therapy and temozolomide for one year. Progression-free survival (PFS) and overall survival (OS) were compared to a control of 58 patients with focal high-grade glioma who received similar therapy, but that included bevacizumab at 10 mg/kg given every two weeks. Results: The patient characteristics were similar in each group. The median PFS and OS for invasive HGG patients were 6 and 13 months and for the focal HGG patients, 11 and 24 months, respectively (P=0.092 and P=0.071). In the subgroup of invasive HGG that showed significant angiogenesis, the median PFS and OS were 3 and 9 months, respectively. 56% of the focal HGG patients recurred as diffuse invasive relapse. For patients with focal HGG who recurred as invasive disease, the median PFS and OS were 9 and 21 months respectively. Conclusions: Presence of diffuse invasive disease not accompanied by angiogenesis either prior to therapy or subsequent to anti-angiogenic therapy does not seem to have prognostic significance. However, invasion accompanied by angiogenesis in newly diagnosed HGG may confer a poor prognosis