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Purpose: Given the excellent prognosis for patients with benign meningiomas, treatment strategies to minimize late effects are important. One strategy is proton radiation therapy (RT), which allows less integral dose to normal tissue and greater homogeneity than photon RT. Here, we report the first series of proton stereotactic radiosurgery (SRS) used for the treatment of meningiomas. Methods and Materials: We identified 50 patients with 51 histologically proven or image- defined, presumed-benign meningiomas treated at our institution between 1996 and 2007. Tumors of =}2 mm from the optic apparatus were eligible for treatment. Indications included primary treatment (n = 32), residual tumor following surgery (n = 8), and recurrent tumor following surgery (n = 10). The median dose delivered was 13 Gray radiobiologic equivalent (Gy[RBE]) (range, 10.0-15.5 Gy[RBE]) prescribed to the 90% isodose line. Results: Median follow-up was 32 months (range, 6-133 months). Magnetic resonance imaging at the most recent follow-up or time of progression revealed 33 meningiomas with stable sizes, 13 meningiomas with decreased size, and 5 meningiomas with increased size. The 3-year actuarial tumor control rate was 94% (95% confidence interval, 77%-98%). Symptoms were improved in 47% (16/ 34) of patients, unchanged inmore » 44% (15/34) of patients, and worse in 9% (3/34) of patients. The rate of potential permanent adverse effects after SRS was 5.9% (3/51 patients). Conclusions: Proton SRS is an effective therapy for small benign meningiomas, with a potentially lower rate of long-term treatment-related morbidity. Longer follow-up is needed to assess durability of tumor control and late effects.« less

Extensive DNA rearrangements occur during the differentiation of the developing somatic macronuclear genome from the germ line micronuclear genome of Tetrahymena thermophila. To identify genes encoding proteins likely to be involved in this process, we devised a cytological screen to find proteins that specifically localize in macronuclear anlagen (Lia proteins) at the stage when rearrangements occur. We compared the localization of these with that of the chromodomain protein, Pdd1p, which is the most abundant known participant in this genome reorganization. We show that in live cells, Pdd1p exhibits dynamic localization, apparently shuttling from the parental to the developing nuclei through cytoplasmic bodies called conjusomes. Visualization of GFP-tagged Pdd1p also highlights the substantial three-dimensional nuclear reorganization in the formation of nuclear foci that occur coincident with DNA rearrangements. We found that late in macronuclear differentiation, four of the newly identified proteins are organized into nuclear foci that also contain Pdd1p. These Lia proteins are encoded by primarily novel genes expressed at the beginning of macronuclear differentiation and have properties or recognizable domains that implicate them in chromatin or nucleic acid binding. Three of the Lia proteins also localize to conjusomes, a result that further implicates this structure in the regulation of DNA rearrangement.

Purpose: To investigate the effects of different imaging artifact correction strategies and susceptibility to setup errors for multiple spinal SBRT planning approaches in treating a patient with titanium hardware. Methods: Two-step-IMRT, IMRT and two arc VMAT plans were created for a C-spine SBRT case with titanium hardware. The plans were normalized to the maximum point dose to the thecal sac. Density overrides for the planning CT were applied to mitigate imaging artifacts. All plans were recalculated on CTs with no density overrides and with the density of all structures set to 1g/cm^3. Setup errors up to 2mm toward the spinal cord were simulated. Results: The 2-step IMRT plans achieved a mean dose to the cord of 6.5Gy compared to 8.0 and 8.7Gy for the IMRT and VMAT plans. The PTV coverage was comparable for both the 2-step-IMRT and the IMRT plan. The VMAT plan achieved a higher mean dose, but had hot spots >130%. If no density overrides were applied for the same MUs the increase in maximum dose to the cord was 0.3, 1.2 and 0.0% for 2-step-IMRT, IMRT and VMAT plans, respectively, compared to an increase of 2.3, 2.0 and 1.0% for unit density override.An isocenter shift of 2mm toward the cord resulted in an increase in maximum dose to the cord of 10.7, 8.0 and 5.0% for the 2-step IMRT, IMRT and VMAT plan, respectively, with the absolute dose to the cord still being lowest for the 2-step-IMRT plan compared to the other plans without simulated setup errors. Conclusion: The 2-step-IMRT plan achieved the clinically most acceptable dose distribution. The plan quality was relatively insensitive to density overrides. The 2-step-IMRT plan was the most sensitive to setup errors due to the steep gradient but this was offset by the initial improvement in sparing of the cord.

e11584 Background: Brain metastases occur late in the course of metastatic breast cancer and the median survival from time of brain metastases has historically been ~4 months. Stereotactic radiosur...

Does prophylactic cranial irradiation reduce the incidence of brain metastases in extensive small-cell lung cancer?

Conclusions: ADT+RT is associated with reduced PCS and overall mortality in real-world clinical practice, consistent with findings from two RCTs. ADT+RT is also associated with reduced mortality in screen-detected and elderly patient subgroups not represented in the RCTs. Author Disclosure: J.E. Bekelman: None. N. Mitra: None. E. Handorf: None. R. Uzzo: None. S. Hahn: None. D. Polsky: None. K. Armstrong: None.

Spatially restricted in vivo expression of the Notch ligands Delta1 and Jagged1 suggests their differential roles in inducing hematopoietic cell fates, and studies have shown that each induces alternative fates during in vitro culture. We hypothesize that the ligands induce alternative fates via differential activation of Notch1 and/or Notch2. To address this, we assessed fate outcomes of Notch1- and Notch2-deficient murine bone marrow derived lin − Sca-1 + c-kit + Hoescht side population progenitors (LSKSP) after 14-days incubation with either purified Delta1 or Jagged1 in serum containing medium. Ligands consisted of purified Delta1 and Jagged1 extracellular domains fused to HumanIgG1 (Delta1 ext-IgG or Jagged1 ext-IgG ). Equal amounts of ligand, as determined by ELISA, were immobilized to plastic surfaces of culture wells along with fibronectin. Notch deficient cells were generated by infecting either Notch1 fl/fl or Notch2 fl/fl LSKSP with lentivirus encoding cre recombinase. We show here that both ligands inhibit myeloid differentiation, since after 14 days, LSKSP incubated with either ligand generated multi-log increased numbers of immature progeny with significantly reduced percentages of GR1 + and/or F480 + cells compared to LSKSP incubated with control-IgG. However, only Delta1 ext-IgG promotes T-cell progenitor differentiation, since a higher percentage of progeny cultured with Delta1 ext-IgG expressed CD25 (37.0+/−0.6%) compared to Jagged1 ext-IgG (1.7+/−1.0%; p=0.01). In contrast, Jagged1 ext-IgG is less effective at inhibiting myeloid differentiation, since a higher percentage of progeny cultured with Jagged1 ext-IgG (2.1+/−0.9%) expressed GR1 and F4/80 compared to Delta1 ext-IgG (56.5+/−6.3; p=0.02). Furthermore, Delta1 ext-IgG is more effective than Jagged1 ext-IgG at inducing Notch activation as measured by increased expression of Notch target Hes1, since we found 3.3-fold more expression of Hes1 mRNA following incubation of LSKSP cells with Delta1 ext-IgG compared to Jagged1 ext-IgG . We further show that Notch2 is required to prevent myeloid differentiation, since Notch2 deficient LSKSP incubated with either Delta1 ext-IgG or Jagged1 ext-IgG generated cultures containing fewer numbers of cells and a higher percentage of GR1 + and/or F480 + myeloid progeny (83% with Delta1 ext-IgG or 86% with Jagged1 ext-IgG ) similarly to those generated with control-IgG. Likewise, we found a reduced percentage of immature Sca-1 + c-kit + cells (19.3+/−4.4 or 13.0+/−5.2) than wild-type cells incubating with Delta1 ext-IgG or Jagged1 ext-IgG (92.2+/−3.0 or 71.0+/−15.0: p=0.004 or p=0.05). We found that Notch1 is required to induce T-cell differentiation, since Notch1 deficient LSKSP incubated with Delta1 ext-IgG had a reduced percentage of CD25 + cells compared to wild-type cells (4.4+/−1.9% to 30.3+/− 3.3) even though myeloid differentiation was inhibited. In summary, we show that both Delta1 ext-IgG and Jagged1 ext-IgG induce signaling via Notch2 to prevent myeloid differentiation, whereas only Delta1 ext-IgG induces signaling via Notch1 to promote generation of T-cell progenitors. Our results indicate unique Notch ligands differentially activate Notch1 or Notch2, resulting in alternative cell fate choices and lay a framework for investigating the mechanisms underlying differential activation, including determining the role of Notch modifiers such as Fringe.

HSCs either self-renew or differentiate to give rise to multipotent cells whose progeny provide blood cell precursors. However, surprisingly little is known about the factors that regulate this choice of self-renewal versus differentiation. One candidate is the Notch signaling pathway, with ex vivo studies suggesting that Notch regulates HSC differentiation, although a functional role for Notch in HSC self-renewal in vivo remains controversial. Here, we have shown that Notch2, and not Notch1, inhibits myeloid differentiation and enhances generation of primitive Sca-1(+)c-kit(+) progenitors following in vitro culture of enriched HSCs with purified Notch ligands. In mice, Notch2 enhanced the rate of formation of short-term repopulating multipotential progenitor cells (MPPs) as well as long-term repopulating HSCs, while delaying myeloid differentiation in BM following injury. However, consistent with previous reports, once homeostasis was achieved, neither Notch1 nor Notch2 affected repopulating cell self-renewal. These data indicate a Notch2-dependent role in assuring orderly repopulation by HSCs, MPPs, myeloid cells, and lymphoid cells during BM regeneration.