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In patients with mantle cell lymphoma (MCL) up to 65 years, recommended first-line treatment consists of immuno-chemotherapy including high-dose cytarabine (HA), followed by autologous stem cell transplantation (ASCT) in complete (CR) or partial remission (PR).1 However, it remains unclear whether total body irradiation (TBI) should be part of conditioning before ASCT.1 A large registry study by the European Society for Blood and Marrow Transplantation (EBMT) including 418 MCL patients reported a significantly reduced relapse incidence after TBI in comparison to a non-TBI conditioning (mostly carmustine, etoposide, cytarabine, and melphalan, BEAM), but only for patients transplanted in first PR.2 In contrast, a single-center evaluation of 73 MCL patients who underwent ASCT did not find a significant PFS difference according to the use of TBI vs BEAM.3 A recently published consensus project by EBMT/European MCL Network involving twelve expert clinicians showed that, while consensus was achieved on ASCT as standard first-line consolidation therapy, no consensus was reached on the role of TBI.4 Three recently completed prospective studies including untreated MCL patients up to 65 years investigated the efficacy of HA-containing immuno-chemotherapy followed by ASCT: Nordic MCL2,5, 6 HOVON-45(ref. 7) and European MCL Younger.8, 9 We combined the individual patient data from these studies to compare the long-term clinical outcome of MCL patients transplanted without TBI (Nordic MCL2 and HOVON-45) vs with TBI (MCL Younger, experimental HA-containing arm).

We studied the effect of decreased glucose concentration on cerebrovascular tone in vitro. Segments of rat middle cerebral arteries (MCA) were isolated, cannulated at both ends with glass micropipettes, and pressurized to 85 mm Hg. Decreasing the glucose in the extraluminal bath and luminal perfusate from 5.5 mmol/L to 1.0 or 0.5 mmol/L for 1.5 hours each had no significant effect on the diameter of the arteries. When all the glucose was removed from the extraluminal bath and luminal perfusate for 1.5 hours, the MCA dilated by 23% [252 ± 24 (SD) μm to 311 ± 7 μm ( P < .5, n = 7)]. This dilation was 80% of the maximum dilation produced by removal of Ca+2 from the bathing solutions. Neither removal of the endothelium nor inhibition of the ATP-sensitive K channels with 10−5 mol/L glibenclamide altered the response of the isolated MCA to the removal of glucose. We conclude that rat MCA are relatively more resistant to substrate limitation compared to the brain as a whole.

Traditionally, the use of ketamine for patients with traumatic brain injuries is contraindicated due to the concern of increasing intracranial pressure (ICP). These concerns, however, originated from early studies and case reports that were inadequately controlled and designed. Recently, the concern of using ketamine in these patients has been challenged by a number of published studies demonstrating that the use of ketamine was safe in these patients. This article reviews the current literature in regards to using ketamine in patients with traumatic brain injuries in different clinical settings associated with anesthesia, as well as reviews the potential mechanisms underlying the neuroprotective effects of ketamine. Studies examining the use of ketamine for induction, maintenance, and sedation in patients with TBI have had promising results. The use of ketamine in a controlled ventilation setting and in combination with other sedative agents has demonstrated no increase in ICP. The role of ketamine as a neuroprotective agent in humans remains inconclusive and adequately powered; randomized controlled trials performed in patients undergoing surgery for traumatic brain injury are necessary.

Introduction High-dose cytarabine containing immuno-chemotherapy followed by autologous stem cell transplantation (ASCT) has been established as standard first-line treatment in younger mantle cell lymphoma (MCL) patients (ESMO guideline, Ann Oncol 2013). However, the role of total body irradiation (TBI) as conditioning regimen for ASCT has not been clarified so far. A retrospective EBMT survey of 418 MCL patients suggested a benefit of TBI with respect to the rate of relapse in patients who achieved a partial remission before ASCT (Rubio et al., ASH 2010). We combined the individual patient data of the Nordic MCL2 trial (Geisler et al., Blood 2008), the HOVON 45 trial (van’t Veer et al., BJH 2008, both without TBI), and the high-dose cytarabine containing study arm of the European MCL Younger trial (Hermine et al., ASH 2012, with TBI) to evaluate potential differences in long term outcome. Methods All trials included patients with advanced stage MCL up to 66 years and a central review of histology. Induction treatment of Nordic MCL2 consisted of 6 alternating courses of Maxi-CHOP or high-dose cytarabine (12g/m2 per cycle, 8g/m2 in patients > 60 years, total cumulative dose 24-36g/m2) combined with 4-6 cycles rituximab, in HOVON 45 three courses R-CHOP were followed by one cycle of high-dose cytarabine (16g/m2), and in MCL Younger patients received 6 alternating courses of R-CHOP or R-DHAP (4g/m2 cytarabine per cycle, total cumulative dose 12g/m2). Conditioning before ASCT consisted of BEAM or BEAC in Nordic MCL2, and BEAM in HOVON 45, whereas a TBI-containing regimen (TAM: 10 Gray TBI, 6g/m2 cytarabine, 140mg/m2 melphalan) was applied in MCL Younger. We compared baseline characteristics, progression free survival (PFS) overall survival (OS) after ASCT from the three patient cohorts with adjustment for MIPI (Hoster et al., Blood 2008) and quality of remission before ASCT. Results In Nordic MCL2, HOVON 45, and MCL Younger 145, 61, and 171 patients were transplanted in complete (CR) or partial (PR) remission (median age 57, 55, and 56 years, p=0.24). According to MIPI, 46%, 56%, and 67% were low risk, whereas 22%, 13%, and 11% were high risk patients (p=0.006). Five-year PFS after ASCT was 61%, 50%, and 78%, respectively (p Conclusion The longer PFS after ASCT of MCL Younger compared to HOVON 45 patients may be due to the different time schedule of cytarabine during induction or to a higher efficacy of TBI vs. BEAM, as the total chemotherapy doses were comparable and we adjusted for MIPI. We could not see an improved PFS after ASCT of MCL Younger compared to Nordic MCL2 patients transplanted in CR or unconfirmed CR and, after adjustment for the different risk profiles, this was also not clearly seen for patients transplanted in PR. Taking into account the substantially higher cytarabine dose in Nordic MCL2 during induction one might speculate that this fact at least partially compensated for a higher efficacy of TBI. Multivariable analyses incorporating additional prognostic factors (Ki-67 and MRD) will help to clarify the impact of the individual parts of the current multimodal approach in younger MCL patients. On behalf of the European Mantle Cell Lymphoma Network Disclosures: No relevant conflicts of interest to declare.

Introduction Mantle cell lymphoma (MCL) is an aggressive B cell lymphoma, previously correlated to a short survival of 3-5 years. Modern clinical protocols, combining immunochemotherapy, high-dose therapy and autologous stem cell transplantation (ASCT) have remarkably improved survival reaching a median survival of more than 10 years. To enable patient stratification, a MCL international prognostic index (MIPI) has been created similar to the international prognostic index (IPI) and follicular lymphoma international prognostic index (FLIPI). However, MIPI alone, or in combination with Ki-67 (MIPI-B), has shown limited use in guiding treatment decisions by poorly separating low and intermediate risk group patients treated with novel clinical protocols. The transcription factor SOX11 has during recent years been shown to be an important diagnostic, prognostic and functional antigen in MCL. We have recently developed a monoclonal antibody to target SOX11 in clinical applications such as IHC and FACS. Using this antibody with improved specificity, we investigated the prognostic use of SOX11 in the homogenously treated Nordic MCL2 and MCL3 cohort. Additionally, we investigated the prognostic value by combining SOX11 and MIPI/MIPI-B. Methods The Nordic MCL2 (n=58) and MCL3 (n=69) patient cohort, treated with first line intensive immunochemotherapy, followed by high-dose chemotherapy and ASCT as well as addition of ibritumomab radioimmunotherapy for MCL3 patients, was stained for SOX11 expression in relation to clinicopathological and biological parameters such as Ki-67, P53 and Cyclin D1. Results In total, 95 % of the Nordic MCL2/3 cohort expressed SOX11, similar to previous studies. The nuclear SOX11 stainings were classified based on both intensity and frequency; negative, weak, strong ≤ 30 % and strong > 30 %. We show that high protein levels of SOX11 (strong > 30 %) correlate to an increased survival among MCL2/3 patients (p=0.02). A positive correlation between SOX11 and Cyclin D1 (p=0.006) was identified while both P53 (p Conclusions We show that the expression level of SOX11 correlates to improved OS in the Nordic MCL2/3 cohort, and this is the first time SOX11 has been correlated to survival in a homogenously treated cohort. Furthermore, the use of SOX11 can separate MIPI low/intermediate patients into two groups with significant difference in OS. SOX11 in combination with MIPI-B defines both a large group of patients with great outcome that benefit from the current treatment and a distinct reduced high risk group of patients with a short survival that potentially should receive alternative treatment. Thus, combining SOX11 status and the MIPI/MIPI-B can be used to stratify patients for treatment selection. Disclosures: No relevant conflicts of interest to declare.

e18567 Background: Mantle cell lymphoma is a disease of the elderly, with a median age of 70 years. Younger patients may be treated with potentially curative treatment including high dose chemother...