Citations

Abstract Sex differences in brain tumor related epilepsy (BTE) as an initial symptom of glioma are rarely investigated. Sex differences are being explored with increased interest more recently. Epidemiological studies have generally indicated overall incidence of epilepsy to be slightly higher in males than females, but a higher incidence of idiopathic generalized epilepsy has been seen in females in some studies. Clinicians regularly face the challenge of anti-epileptic drug prescription determination in patients with newly identified brain mass and would greatly benefit from knowing clinical characteristics in BTE. We analyzed clinical characteristics in patients with pathologically-determined glioma with known seizure status at clinical presentation using non-parametric and Fisher’s Exact tests with the entire cohort and male and female separately. From our clinical data repository, we identified 223 patients (females, n=86 (39%); males, n=137 (61%)) divided by those that presented with seizure (SP, n=96, 43%; F, n= 28; M, n= 68) and those that presented without seizure (nSP, n=127, 57%, F n=58, M n=69). In sex-specific analysis males had a significantly (x2=6.28, p=0.01) higher proportion of SP (49.6%) than females (32.6%). There was a dependence between seizure presentation status and tumor grade in males (x2=5.94, p=0.015). Tumor kinetics in the female cohort showed significantly (p< 0.0001) more diffuse tumors in SP compared to nSP. Right-sided tumors were predominantly nSP, while left-sided tumors were split more evenly between SP and nSP. The predominance of nSP among right-sided tumors seems to be driven by females (74%), male right-sided tumors were split more evenly between SP and nSP. Seizure status is dependent on tumor location for the combined cohort, however not for males (x2=5.23, p=0.16) or females (x2=4.34, p=0.23). Clearly there are sex differences and similarities in clinical characteristics at glioma presentation. Further characterization could lead to improved adherence of national standards for AED prescription.

AbstractNuclear actin plays a critical role in mediating mesenchymal stem cell (MSC) fate commitment. In marrow-derived MSCs, the principal diaphanous-related formin Diaph3 (mDia2) is present in the nucleus and regulates intranuclear actin polymerization, whereas Diaph1 (mDia1) is localized to the cytoplasm and controls cytoplasmic actin polymerization. We here show that mDia2 can be used as a tool to query actin-lamin nucleoskeletal structure. Silencing mDia2 affected the nucleoskeletal lamin scaffold, altering nuclear morphology without affecting cytoplasmic actin cytoskeleton, and promoted MSC differentiation. Attempting to target intranuclear actin polymerization by silencing mDia2 led to a profound loss in lamin B1 nuclear envelope structure and integrity, increased nuclear height, and reduced nuclear stiffness without compensatory changes in other actin nucleation factors. Loss of mDia2 with the associated loss in lamin B1 promoted Runx2 transcription and robust osteogenic differentiation and suppressed adipogenic differentiation. Hence, mDia2 is a potent tool to query intranuclear actin-lamin nucleoskeletal structure, and its presence serves to retain multipotent stromal cells in an undifferentiated state.

There are many kidney diseases that might be addressed by gene therapy. However, gene delivery to kidney cells is inefficient. This is due, in part, to the fact that the kidney excludes molecules above 50 kDa and that most gene delivery vectors are megaDaltons in mass. We compared the ability of adeno-associated virus (AAV), adenovirus (Ad), and lentiviral (LV) vectors to deliver genes to renal cells. When vectors were delivered by the intravenous (IV) route in mice, weak luciferase activity was observed in the kidney with substantially more in the liver. When gene delivery was observed in the kidney, expression was primarily in the glomerulus. To avoid these limitations, vectors were injected directly into the kidney by retrograde ureteral (RU) and subcapsular (SC) injections in mice. Small AAV vectors transduced the kidney, but also leaked from the organ and mediated higher levels of transduction in off-target tissues. Comparison of AAV2, 6.2, 8, and rh10 vectors by direct kidney injection demonstrated highest delivery by AAV6.2 and 8. Larger Ad and LV vectors transduced kidney cells and mediated less off-target tissue transduction. These data demonstrate the utility of direct kidney injections to circumvent the kidney size exclusion barrier. They also identify the effects of vector size on on-target and off-target transduction. This lays the foundation for the use of different vector platforms for gene therapy of diverse kidney diseases.

The development of multiple highly effective and safe direct-acting antivirals to treat hepatitis C virus (HCV) has resulted in greater ease and confidence in managing HCV infection in transplant recipients that in turn has impacted the solid organ transplant community as well. In the United States, the opioid epidemic has increased the number of overdose deaths with a concomitant increase in younger HCV viremic donors after brain death being identified. At the same time, a decrease in HCV viremic transplant candidates has led to a growing interest in exploring the use of HCV viremic liver and kidney donor allografts in HCV-negative recipients. To date, experience with the use of HCV viremic liver and kidney allografts in HCV-negative recipients is limited to a few small prospective research trials, case series, and case reports. There are also limited data on recipient and donor selection for HCV viremic liver and kidney allografts. In response to this rapidly changing landscape in the United States, experts in the field of viral hepatitis and liver and kidney transplantation convened a meeting to review current data on liver and kidney recipient selection and developed consensus opinions related specifically to recipient and donor selection of HCV viremic liver and kidney allografts.

Abstract The inhibitory effects exerted by transforming growth factor-β (TGF-β) on adult erythropoiesis has been well established. Canonical SMAD-depedent TGF-β signaling inhibits erythroid differentiation at multiple levels: it induces hematopoietic stem cells into quiescence (Chabanon et at Stem Cells. 2008;26:3150), it elicits a Smad5-dependent inhibition of progenitor cell proliferation (Bruno et al, Blood 1998; 91:1971) by increasing the length of G1 through reduction of G1 cyclin and cyclin-dependent protein kinases (Jacobsen et al, Blood 1995; 86:2957; Geng and Weinberg, PNAS 1993; 90:10315) and triggers Smad4-signaling accelerating terminal erythroid maturation (Zermati et al, Exp hematol 2000; 28:885; Choi et al MCB 2005;271:23). TGF-β is expressed by almost every cell type, but is produced in the greatest amount by megakaryocytes (Assonian et al, JBC 1983;258:7155; Massague, Cell 2008;134, 215). TGF-β has been implicated in the pathogenesis of primary myelofibrosis (PMF) by Schmitt et al (Blood. 2000;96:1342). Plasma, bone marrow and spleen washes of PMF patients, as well as those from murine PMF models, contain 2 fold-greater levels of total and bioactive TGF-β than those from normal controls (Zingariello et al, Blood 2013;121:3345). In addition, megakaryocytes from PMFpatients contain greater amounts of TGF-β than those from other MPNs such as polycythemia vera (PV) and essential thrombocythemia (Ciurea et al, Blood 2007;110:986). Published data, however, also suggest that malignant MPN cells are insensitive to TGF-β. Microarray analyses of PMF bone marrow and spleen cells revealed TGF-β signaling abnormalities which predict activation of non-canonical p38/ERK-dependent rather than canonical SMAD-dependent signaling (Ciaffoni et al, BCMD 2015;54:234). In addition, by phosphoproteomic profiling of PV erythroblasts (Erys) expanded in vitro express lower levels of pSmad2 as compared to Erys from healthy controls (Hricik et al. AJH 2013;88:723). The hypothesis that malignant MPN cells are insensitive to TGF-β was tested here by evaluating the effect of SB431542 [1,3,10 and 26µM], a small molecule inhibitor of TGF-β receptor 1, on ex vivo erythropoiesis in cultures generated by peripheral blood mononuclear cells from patients with JAK2 V617+-PV (n=2) and JAK2 V617F+ or CALR pQ365f+-PMF. Identical experiments were performed with Erys generated from adult peripheral blood (AB, n=3) and cord blood (CB, n=2) of healthy controls. All cultures were stimulated with SCF, IL-3 and EPO with and without dexamethasone (Dex). In cultures of JAK2 V617F+ -PV, SB431542 increased by 2-fold the numbers of progenitor cells observed by day 6, but had no effect on that of Erys observed by day 12-17 [fold increase (FI) ~4 fold in all cases]. Moreover, neither the number of progenitor cells nor that of Erys were affected by SB431542 treatment in cultures generated from JAK2 V617F+ (n=1) and CALR pQ365fs+ -PMF (n=1) patients (Fig. 1). This lack of effects was observed in cultures with and without Dex. By contrast, as expected, in cultures of AB, SB431542 significantly increased by 2.5-fold the number of progenitor cells observed by day 6 and that of Erys observed by day 14-17 (Fig. 1). This increase was associated with greater retention of an immature erythroid phenotype (CD36+ CD235a+ cells 16% vs 3%) and an increased proliferative index (>3 Erys in metaphases per field vs 0). This was observed up to day 17 in cultures both with and without Dex. The effects of SB431542 in cultures of CB were, however, affected by the presence of Dex. In cultures without Dex, SB431542 increased by 2-fold the number of progenitor cells by day 6 but had no effect on that of Erys by day 12-17 (FI=10-15 and CD36+CD235a+ cells >60%). In the presence of Dex, SB431542 did not affect the number of progenitor cells at day 6 but reduced that of Erys by 3-fold on day 12-17. These results suggest that in the case of CB, TGF-β promotes erythroid maturation in synergy with Dex. In conclusion, SB431542 promoted proliferation and maturation of normal adult progenitor cells but had no effect on PMF progenitor cells suggesting that treatments with TGF-β receptor 1 inhibitors may reactivate normal hematopoiesis in PMF patients by providing a proliferative advantage to the resident non-diseased hematopoietic stem cells over the malignant clone. This therapeutic approach will be explored in a MPD-RC, multi-center, phase II trial in patients with PMF. Disclosures Hoffman: Geron: Consultancy, Membership on an entity's Board of Directors or advisory committees; All Cells, LLC: Consultancy, Membership on an entity's Board of Directors or advisory committees; Promedior: Research Funding. Mascarenhas:Roche: Research Funding; Incyte Corporation: Research Funding; Kalobios: Research Funding; CTI Biopharma: Research Funding; Novartis Pharmaceuticals Corporation: Research Funding; Promedior: Research Funding.

Abstract Background Rituximab in combination with chemotherapy has been shown to improve overall survival (OS) in pts with FL compared with chemotherapy alone. The effect of MR was evaluated in randomized clinical trials (RCTs) with conflicting results regarding OS. In a previous systematic review and meta-analysis of summary (aggregate) data we demonstrated an OS benefit of MR treatment in pts with relapsed or refractory FL and an improved progression free survival (PFS) in both untreated and relapsed refractory FL. However, pts' disease and treatment characteristics may interact with the effect of MR. To improve identification of sub-groups of pts who may benefit from MR treatment, and to evaluate factors that interact with the effect of MR we conducted an international IPD (raw data) meta-analysis of RCTs of MR for pts with FL. We present the first analysis of this meta-database. Methods In June 2014, we updated an electronic search in Pubmed and the Cochrane Library, conference proceedings and database of clinical trials for randomized trials comparing MR to observation. The investigators of eleven trials that fulfilled inclusion criteria were invited to cooperate. Results of one trial were not reported and this trial could not be included in the meta-analysis. Seven study groups participated in this collaborative project and contributed data on individual pts, including disease characteristics, past treatment, response, survival and adverse events. We examined the effect of pt, disease and treatment characteristics by performing a series of Cox regression analyses stratified by trial. In a sensitivity analysis we combined the assessed log hazard ratios (HR) using a log-rank test for each study and combined the results using a fixed effect meta-analysis. Results We obtained data for 2323 patients randomized in 7 trials of MR compared to observation after induction therapy. The median follow up ranged from 28-114 months. The median age was 57 years (23 - 85 years), and 41% were older than 60 years. 50% of pts were women, 97% had WHO performance status 0-1; 1195 (53%) pts received CHOP/RCHOP, 453 (20%) CVP/R CVP; 1755 (77%) received rituximab containing induction; 33% of pts received 1st induction, 67% ≥2nd. Overall, pts less than 60 years of age (vs. ≥60 years) (p < 0.0001), and women (p = 0.001) had a better prognosis. There was no interaction between sex and the effect of MR (p = 0.65). Pts treated with MR had an improved OS compared to observation (HR 0.76, 95% CI 0.62-0.93, p=0.008, Figure). This was demonstrated also in a sensitivity analysis of 10 studies fulfilling inclusion criteria. There was no statistically significant heterogeneity of treatment effect between trials (p=0.15). In an analysis by treatment line (1st vs. ≥2nd), the estimated effect of MR among patients who received ≥2nd induction was HR of 0.70 (95% CI 0.55 - 0.91), compared to 0.90 (95% CI 0.65 - 1.25) among patients who received 1st induction. However, this difference was not statistically significant (p=0.25). Analysis by the inclusion of rituximab in induction demonstrated among patients who received rituximab in induction a HR of 0.82 (95% CI 0.63 – 1.06), and among those who received induction without rituximab a HR of 0.68 (95% CI 0.49 – 0.93). This difference was not statistically significant (p= 0.35). Analysis by chemotherapy regimen demonstrated an estimated effect for MR among patients who received RCHOP/CHOP of 0.79, 95% CI 0.58 – 1.06, and after RCVP/CVP of 0.65, 95% CI 0.42 – 1.02, with no statistically significant difference between these sub-groups (p = 0.50). Conclusions This is the first report of the collaborative group of maintenance therapy for FL patients. Based on individual patient data, this study demonstrated an improved OS with MR therapy for patients with FL. A sensitivity analysis with all 10 eligible trials supported these results. Results support the effectiveness of MR among patients after their 1st induction as well as after ≥2nd induction, and irrespective of inclusion of rituximab in induction, and the chemotherapy regimen. These results are consistent with those of the summary data meta-analysis that was previously published. The wider CI and lack of statistical significance within sub-groups could be attributed to the sample size. Figure: Pooled HR of death of MR compared to observation in patients with follicular lymphoma. In one study there were no events in one group and it is not represented in the forest plot. Figure:. Pooled HR of death of MR compared to observation in patients with follicular lymphoma. In one study there were no events in one group and it is not represented in the forest plot. Disclosures Vidal: Roche: unrestricted grant Other. Shpilberg:Roche: Consultancy, Research Funding.

Abstract Abstract 1710 Poster Board I-736 Introduction Treatment regimens for cancer are typically based on cytotoxic chemotherapy, which is poorly tolerated. There is an unmet medical need for new therapies that retain efficacy, but combine this with an improved safety and tolerability profile. Vorinostat is a histone deacetylase (HDAC) inhibitor, approved in the United States for the treatment of cutaneous manifestations of cutaneous T-cell lymphoma (CTCL) in patients who have progressive, persistent, or recurrent disease on or following 2 systemic therapies. Vorinostat is also being investigated as a treatment for various other solid and hematologic malignancies, in which HDACs are further implicated as key regulators of transcription. Herein we present an overview of the safety and tolerability profile of vorinostat, gathered from prior clinical experience. Methods Safety and tolerability data, including adverse events (AEs), QTc interval data and incidence of thromboembolic events (TEE), were collated from patients who received vorinostat, administered as monotherapy or in combination therapy for solid or hematologic malignancies. Results (adverse events) In Phase I and II clinical trials, 498 patients who received vorinostat were analyzed. A total of 341 patients received vorinostat monotherapy (107 with CTCL, 105 other hematologic malignancies, 129 solid tumors) and the most common drug-related AEs in this group were: fatigue (61.9%), nausea (55.7%), diarrhea (49.3%), anorexia (48.1%), and vomiting (32.8%); Grade 3/4 AEs included fatigue (12.0%) and thrombocytopenia (10.6%), and 3 drug-related deaths (ischemic stroke, tumor hemorrhage, unspecified) occurred. Thirty-eight patients (11.1%) discontinued due to drug-related AEs, 71 patients (20.8%) required dose modifications, and 1 patient (0.3%) discontinued due to Grade 2 chest pain. The remaining 157 patients received vorinostat combination therapy (with pemetrexed/cisplatin for advanced cancer [n=46], bortezomib for multiple myeloma [n=34], bexarotene for CTCL [n=23], and erlotinib [n=30], gemcitabine/platin [n=21] or carboplatin/paclitaxel [n=3] for non-small-cell lung cancer). The most common drug-related AEs in this group were: nausea (48.4%), diarrhea (40.8%), fatigue (34.4%), and vomiting (31.2%); the most common Grade 3/4 AE was fatigue (13.4%), and 1 drug-related death (hemoptysis) occurred. Thirty-one patients (19.7%) discontinued due to drug-related AEs and 27 patients (17.2%) required dose modifications. Results (QTcF interval) A trial of 24 patients with advanced cancer was undertaken for rigorous assessment of QTcF interval. In this trial, a single supratherapeutic 800 mg dose of vorinostat did not prolong QTcF interval (monitored over 24 hours). The upper limit of the 90% confidence interval for the placebo-adjusted mean change-from-baseline of vorinostat was <10 msec at every timepoint, no patient had a QTcF change-from-baseline value >30 msec, and 1 patient had a QTcF interval >450 msec (after both vorinostat and placebo administration). The most common drug-related AE in this trial was nausea. There were no serious clinical or laboratory AEs, no discontinuations due to an AE and no patients experienced a cardiac-related AE. Results (incidence of TEE) A review of vorinostat clinical trials, published literature and post-marketing surveillance reports was conducted by a committee of independent academic experts to determine the incidence of TEE in cancer patients who had received vorinostat. In >1845 patients reviewed through November 3, 2008, 107 patients (<5.8%) reported TEE as a serious AE (SAE), 47 (<2.6%) of which were recorded as being related to vorinostat, and 4/47 (<0.3%) TEE SAEs were fatal. Conclusions In this review, the majority of observed AEs were 'Grade 2, there was no observed prolongation of the QTcF interval, and the incidence of TEE with vorinostat was similar to reported rates of TEE in advanced cancer patients. Vorinostat is generally well tolerated when administered as monotherapy or in a combination regimen in cancer patients. Disclosures Siegel: Millennium: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celegne: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Rubin:Merck: Employment, Equity Ownership. Iwamoto:Merck: Employment, Equity Ownership. Hussein:Celgene: Employment. Belani:Merck: Consultancy. Hardwick:Merck: Employment, Equity Ownership. Rizvi:Merck: Employment, Equity Ownership.

Abstract Background : Sex is recognized as a significant determinant of outcome among glioblastoma patients, but the relative prognostic importance of glioblastoma features has not been thoroughly explored for sex differences. Methods : Combining multi-modal MR images, biomathematical models, and patient clinical information, this investigation assesses which pretreatment variables have a sex-specific impact on the survival of glioblastoma patients (299 males and 195 females). Results : Among males, tumor (T1Gd) radius was a predictor of overall survival (HR=1.027, p=0.044). Among females, higher tumor cell net invasion rate was a significant detriment to overall survival (HR=1.011, p<0.001). Female extreme survivors had significantly smaller tumors (T1Gd) (p=0.010 t-test), but tumor size was not correlated with female overall survival (p=0.955 CPH). Both male and female extreme survivors had significantly lower tumor cell net proliferation rates than other patients (M p=0.004, F p=0.001, t-test). Additionally, extent of resection, tumor laterality, and IDH1 mutation status were also found to have sex-specific effects on overall survival. Conclusion : Despite similar distributions of the MR imaging parameters between males and females, there was a sex-specific difference in how these parameters related to outcomes.

Abstract Background: Sex is recognized as a significant determinant of outcome among glioblastoma patients, but the relative prognostic importance of glioblastoma features has not been thoroughly explored for sex differences. Methods: Combining multi-modal MR images, biomathematical models, and patient clinical information, this investigation assesses which pretreatment variables have a sex-specific impact on the survival of glioblastoma patients (299 males and 195 females). Results: Among males, tumor (T1Gd) radius was a predictor of overall survival (HR=1.027, p=0.044). Among females, higher tumor cell net invasion rate was a significant detriment to overall survival (HR=1.011, p<0.001). Female extreme survivors had significantly smaller tumors (T1Gd) (p=0.010 t-test), but tumor size was not correlated with female overall survival (p=0.955 CPH). Both male and female extreme survivors had significantly lower tumor cell net proliferation rates than other patients (M p=0.004, F p=0.001, t-test). Additionally, extent of resection, tumor laterality, and IDH1 mutation status were also found to have sex-specific effects on overall survival. Conclusion: Despite similar distributions of the MR imaging parameters between males and females, there was a sex-specific difference in how these parameters related to outcomes.