Citations

OBJECTIVE Tumor-associated macrophages (TAMs) have been implicated as pathologic actors in phenotypically aggressive vestibular schwannoma (VS), potentially mediated via programmed death-ligand 1 (PD-L1). The authors hypothesized that PD-L1 is a key regulator of the VS immune microenvironment. METHODS Forty-six consecutive, radiation-naïve, sporadic VSs that were subtotally resected at primary surgery were assessed via immunohistochemical analysis, including analysis of CD163 and PD-L1 expression. Pathologic data were correlated with clinical endpoints, including tumor control, facial nerve function, and complications. RESULTS Baseline parameters were equivalent between stable and progressive post–subtotal resection (STR) VS. CD163 percent positivity and M2 index were significantly increased among tumors that remained stable (34% vs 21%, p = 0.02; 1.13 vs 0.99, p = 0.0008), as well as patients with favorable House-Brackmann grade I or II facial nerve function (31% vs 13%, p = 0.04; 1.11 vs 0.97, p = 0.05). PD-L1 percent positivity was significantly associated with tumor progression (1% vs 11%, p = 0.01) and unfavorable House-Brackmann grade III–VI facial nerve function (1% vs 38%, p = 0.02). On multivariate analysis, PD-L1 was independently significant in all models (likelihood ratio 4.4, p = 0.04), while CD163 was dependent in all iterations. CONCLUSIONS In contrast to prior reports, in this study, the authors observed significantly increased levels of M1, CD163 + TAMs in association with VS that progressed after STR. Progressive tumors are characterized by increased PD-L1, potentially highlighting a mechanism of immune evasion that results in TAM deactivation, tumor growth, and further infiltration of anti-tumor immune cells. Targeting PD-1/PD-L1 may offer therapeutic promise, particularly in the setting of disease control after STR.

Abstract Abstract 3972 Background: The treatment paradigm for myeloma has undergone a dramatic shift in the past decade with the introduction of the novel agents and their application at every stage of the treatment. We and others had previously shown that survival of patients with myeloma had improved in the earlier half of the last decade and attributed this to a combination of novel therapies as well as increased use of stem cell transplant. It is not clear if this momentum in improving survival has been maintained. We examined the survival trends of patients with newly diagnosed myeloma seen within the past decade to examine this question. Patients and Methods: We studied 1056 patients with newly diagnosed myeloma, who were seen at Mayo Clinic between January 1, 2001 and December 31, 2010; who were seen within 30 days of their diagnosis. For examination of the time trends, we grouped the time interval into two five year periods, 2001–2005 and 2006–2010. Survival was estimated using Kaplan Meier method and survival curves were compared by log rank test. Impact of various prognostic factors was evaluated using Cox proportional hazards test. Results: The median age at diagnosis was 65 (range; 22–92), and 59% were male. The median estimated follow up for the entire cohort was 4.6 years (95% CI; 4.4, 4.9) and 57% of the patients were alive at last follow up. The median overall survival (OS) for the entire cohort was 5.4 years (95% CI; 5, 6.3). The overall survival for patients in the 2001–2005 group was 4.6 years compared with not reached for the 2006–2010 cohort (P< 0.001). The five-year estimated OS was 48% for the earlier group compared with 66% for the latter group. The estimated 1-year survival was 90% for the recent cohort compared with 83% for the earlier cohort, suggesting improvements in the early mortality. Interestingly, the improvement was predominantly seen in the older age group (>65 years; 49%). The 5-year survival of the older patients improved significantly from 31% (2001–2005) to 56% (2006–2010) (P<0.001). In contrast, among younger patients (≤65 years of age), the 5-year survival improved only marginally from 63% (2001–2005) to 73% (2006–2010) (P=NS). One or more novel agents (Lenalidomide, thalidomide or bortezomib) were used as part of initial therapy in 631 (62% of 1021 in whom treatment data was available). The OS among of this group was 7.3 years (95% CI; 5.9, NR) compared with 3.8 years (95% CI; 3.1, 4.6). In a multivariate model that included both use of novel agent and the year group, only the novel agent use was associated with improved survival suggesting that the improvement in the survival is related to the increased use of novel agents in the initial therapy. No significant differences were observed between the groups in terms of conventional prognostic factors. Conclusions: The current results confirm continued improvement in the overall survival of patients, even within the last 10 year period, and highlight the impact of initial therapy with novel agents. Most importantly, we demonstrate that the improved survival has primarily benefited older patients. Our study highlights that urgent need for additional new agents to provide further survival improvement for younger patients, and in order achieve a cure for this disease. Disclosures: Kumar: Merck: Consultancy, Honoraria; Celgene: Research Funding; Millennium: Research Funding; Novartis: Research Funding; Cephalon: Research Funding; Genzyme: Research Funding. Dispenzieri:Celgene: Research Funding; Millennium Pharmaceuticals, Inc.: Research Funding; Janssen Research & Development: Research Funding. Gertz:Binding Site: Honoraria.

Abstract Abstract 4000 Background: We have previously reported that there is an increased risk of monoclonal gammopathy of undetermined significance (MGUS) in first-degree relatives of patients with multiple myeloma (Vachon CM. Blood 2009 114: 785–790). There are several cytogenetic subtypes of myeloma, and there are no data on whether certain cytogenetic subtypes of myeloma are more frequently associated with familial MGUS. Methods: We studied patients with myeloma who participated in the familial MGUS study in whom presence or absence of MGUS in the first-degree relatives had been ascertained (Vachon CM. Blood 2009 114: 785–790). Probands were seen at the Mayo Clinic Hematology/Oncology practice (Rochester, MN, USA) between February 2006 and September 2007. Cytogenetic data was acquired via electronic medical record abstraction of fluorescence in-situ hybridization (FISH) lab reports, and used to categorize patients into one of nine cytogenetic subgroups: trisomy(ies), t(6;14), t(11;14), t(4;14), t(14;16), t(14;20), Mixed (those with trisomy(ies) and an IgH translocation), other cytogenetic abnormalities (in the absence of trisomy(ies) or IgH translocation), and normal (Kumar S. Blood 2012;119:2100–2105). We examined whether a difference in the distribution of the six primary cytogenetic categories of myeloma existed between probands with a family history of MGUS and/or myeloma and those without. Results and Conclusions: Of the 248 patients invited to participate, FISH data (with sufficient plasma cells) was available on 119 participants to establish the primary molecular cytogenetic classification of myeloma. All had available information regarding family history of MGUS and multiple myeloma. 27 had an affected first-degree relative with MGUS, and 92 did not. Distributions of cytogenetic subtypes in the two groups are shown in Table 1. IgH translocated MM was more common in myeloma patients who lacked an affected first-degree relative compared to those with familial MGUS (19% vs 30%, P=0.32) Interestingly, the t(11;14) subtype was more common in myeloma patients without familial MGUS compared to those with an first-degree relative with MGUS (19.6% vs 7.4%, P=0.24). The differences in Table 1 did not reach statistical significance, possibly due to the small numbers of individuals with a family history in this sample. However, the distribution (Table 1) suggests that the distribution of cytogenetic subtypes may be different in myeloma that is not associated with familial MGUS compared with myeloma in which a familial tendency is detected. IgH translocated MM appears to have a lower risk of familial tendency. Further investigation is needed to estimate the risk of familial MGUS within each cytogenetic subtype. Disclosures: Kumar: Merck: Consultancy, Honoraria; Millennium: Research Funding; Celgene: Consultancy, Research Funding; Novartis: Research Funding; Genzyme: Research Funding.

Glioblastoma (GBM; grade 4 glioma) is a highly aggressive and incurable tumor. GBM has recently been characterized as highly dependent on alternative splicing, a critical driver of tumor heterogeneity and plasticity. Estrogen‐related receptor β (ERR‐β) is an orphan nuclear receptor expressed in the brain, where alternative splicing of the 3' end of the pre‐mRNA leads to the production of 3 validated ERR‐β protein products: ERR‐β short form (ERR‐βsf), ERR‐β2, and ERR‐β exon 10 deleted. Our prior studies have shown the ERR‐β2 isoform to play a role in G 2 /M cell cycle arrest and induction of apoptosis, in contrast to the function of the shorter ERR‐βsf isoform in senescence and G 1 cell cycle arrest. In this study, we sought to better define the role of the proapoptotic ERR‐β2 isoform in GBM. We show that the ERR‐β2 isoform is located not only in the nucleus but also in the cytoplasm. ERR‐β2 suppresses GBM cell migration and interacts with the actin nucleation‐promoting factor cortactin, and an ERR‐β agonist is able to remodel the actin cytoskeleton and similarly suppress GBM cell migration. We further show that inhibition of the splicing regulatory cdc2‐like kinases in combination with an ERR‐β agonist shifts isoform expression in favor of ERR‐β2 and potentiates inhibition of growth and migration in GBM cells and intracranial tumors.—Tiek, D. M., Khatib, S. A., Trepicchio, C. J., Heckler, M. M., Divekar, S. D., Sarkaria, J. N., Glasgow, E., Riggins, R. B. Estrogen‐related receptor β activation and isoform shifting by cdc2‐like kinase inhibition restricts migration and intracranial tumor growth in glioblastoma. FASEB J. 33, 13476–13491 (2019). www.fasebj.org

Abstract Context The CD40-CD154 co-stimulatory pathway plays an important role in the pathogenesis of Graves disease (GD) by promoting autoreactive B-cell activation. Objective Evaluate efficacy and safety of a human, blocking, nondepleting anti-CD40 monoclonal antibody, iscalimab, in hyperthyroid patients with GD. Design Open-label, phase II proof-of-concept study. Setting Multicenter. Patients Fifteen with GD. Intervention Patients received 5 doses of iscalimab at 10 mg/kg intravenously over 12 weeks. Main outcome measures Thyroid-related hormones and autoantibodies, plasma soluble CD40, free CD40 on B cells, soluble CXCL13, pharmacokinetics, and safety were assessed. Results The iscalimab intervention resulted in complete CD40 engagement for up to 20 weeks. A clinical response and biochemical euthyroidism was observed in 7 of 15 (47%) patients. Free and total triiodothyronine and thyroxine normalized in 7 patients who did not receive any rescue medication with antithyroid drugs (ATD), and 2/15 (13.3%) showed normal thyrotropin. Six (40%) patients required ATD. Four of 7 responders relapsed after treatment completion. Serum concentrations of thyrotropin receptor autoantibodies (TSH-R-Ab) significantly declined in all patients (mean 15.3 IU/L vs 4.0 IU/L, 66% reduction; P &lt; 0.001) and TSH-R-Ab levels normalized in 4 (27%). Thyroperoxidase and thyroglobulin autoantibodies significantly decreased in responders. Iscalimab rapidly reduced serum CXCL13 concentrations (P &lt; 0.001). Twelve (80.0%) patients reported at least 1 adverse event (AE). All treatment-related AE were mild or moderate and resolved by end of the study. Conclusion Iscalimab was generally safe and clinically effective in a subgroup of hyperthyroid GD patients. The potential therapeutic benefit of iscalimab should be further tested.

Abstract Context The CD40-CD154 co-stimulatory pathway plays an important role in the pathogenesis of Graves’ disease (GD) by promoting auto-reactive B cell activation. Objective Evaluate efficacy and safety of a human, blocking, non-depleting anti-CD40 monoclonal antibody, iscalimab, in hyperthyroid patients with GD Design Open label, phase II proof-of-concept study Setting Multicenter Patients Fifteen with GD Intervention Patients received five doses of iscalimab at 10 mg/kg intravenously over 12 weeks. Main outcome measures Thyroid-related hormones and autoantibodies, plasma soluble CD40, free CD40 on B cells, soluble CXCL13, pharmacokinetics, and safety were assessed. Results The iscalimab intervention resulted in complete CD40 engagement for up to 20 weeks. A clinical response and biochemical euthyroidism was observed in seven of 15 (47%) patients. Free and total T3 and T4 normalized in seven patients who did not receive any rescue medication with anti-thyroid drugs (ATD), and 2/15 (13.3%) showed normal TSH. Six (40%) patients required ATD. Four of seven responders relapsed after treatment completion. Serum concentrations of thyrotropin receptor autoantibodies (TSH-R-Ab) significantly declined in all patients (mean 15.3 IU/L versus 4.0 IU/L, 66% reduction, P<0.001) and TSH-R-Ab levels normalized in four (27%). Thyroperoxidase and thyroglobulin autoantibodies significantly decreased in responders. Iscalimab rapidly reduced serum CXCL13 concentrations (P<0.001). Twelve (80.0%) patients reported at least one adverse event (AE). All treatment-related AE were mild or moderate and resolved by end of the study. Conclusion Iscalimab was generally safe and clinically effective in a subgroup of hyperthyroid GD patients. The potential therapeutic benefit of Iscalimab should be further tested.

Objective: The etiology of sensorineural hearing loss (SNHL) in patients with jugular paraganglioma (JP) whose tumors lack inner ear fistulae or vestibulocochlear nerve involvement is unknown. Recent literature has proposed that occlusion of the inferior cochlear vein may be causative. Herein, we assess the association between radiologic involvement of the cochlear aqueduct (CA) and the development of SNHL. Study Design: Blinded, retrospective review of imaging and audiometry. Setting: Tertiary center. Patients: Adults with JP. Intervention(s): None. Main Outcome Measures: Asymmetric SNHL was assessed continuously as the difference in bone conduction pure-tone average (BCPTA) between ears and as a categorical variable (≥15 dB difference at two consecutive frequencies, or a difference in speech discrimination score of ≥15%). Involvement of the CA was considered present if there was evidence of medial T2 fluid signal loss, contrast enhancement, or bony erosion/expansion. Results: Of 30 patients meeting inclusion criteria, 15 (50%) had asymmetric SNHL. CA involvement was observed in 87% of patients with asymmetric SNHL compared with 13% in those with symmetric hearing (p = 0.0001). Univariate analysis demonstrated that age, sex, and tumor volume were not associated with asymmetric SNHL. The median difference in BCPTA between ears in patients with CA involvement was 21.3 dB HL compared to 1.2 dB HL in those without CA involvement (p < 0.0001). Regression analysis demonstrates that enhancement within the CA is associated with a BCPTA difference of 19.4 dB HL (p = 0.0006). Conclusions: Cochlear aqueduct involvement by JP is associated with SNHL in the absence of inner ear fistula, vestibulocochlear nerve involvement, or brainstem compression. Correlation with operative findings or histopathologic evidence of tumor involvement may validate this intriguing imaging finding.

Background and Purpose— Several angiographic factors of dural arteriovenous fistulas (dAVFs) are associated with aggressive presentation and poor natural history. We examined the association of magnetic resonance imaging T2-weighted-Fluid-Attenuated Inversion Recovery (T2/FLAIR) hyperintensity with aggressive presentation. Methods— A cohort of dAVF patients from 2 centers was retrospectively examined. T2/FLAIR hyperintensity was determined by blinded, de-identified review and compared with angiographic grade and presenting symptoms. Results— T2/FLAIR hyperintensity was only identified in dAVF patients with cortical venous drainage (CVD). Among patients with CVD, those with T2/FLAIR hyperintensity were more likely to present with aggressive symptoms (20/23, 87.0%) than those without (6/21, 28.5%), P <0.001. All cured dAVFs with symptom resolution and available post-treatment imaging had resolution of T2/FLAIR hyperintensity. Conclusions— T2/FLAIR hyperintensity strongly correlates with aggressive presentation and CVD in dAVF patients, and may identify a subset that would benefit from early treatment.