Citations

Objective: To evaluate quality-of-life (QOL) in patients with sporadic vestibular schwannoma (VS) with particular focus on those recently diagnosed. Study Design: Cross-sectional survey, Penn Acoustic Neuroma Quality of Life (PANQOL) instrument. Setting: Acoustic Neuroma Association and a single tertiary referral center. Patients: Patients with sporadic VS. Main Outcome Measures: Domain-specific and total PANQOL scores comparing treatment modalities after adjusting for baseline covariates of interest. Results: Among all 1,288 respondents there were 229 (18%) who were recently diagnosed and had not yet selected a treatment modality, 303 (24%) who were observed, 185 (14%) who underwent radiosurgery alone, 507 (39%) who underwent microsurgery alone, and 64 (5%) who underwent radiosurgery and microsurgery. After adjusting for covariates of interest, total PANQOL scores were highest for the observation cohort (65; 95% CI 62–68), lowest for patients treated with multimodality therapy (56; 51–61) and those recently diagnosed (58; 55–62), and intermediate for those who received microsurgery alone (60; 58–62) and radiosurgery alone (61; 57–64) (global comparison, p = 0.001). When comparing groups that received single-modality therapy, there were no statistically significant differences in total PANQOL scores at short (0–5 yr), intermediate (6–10 yr), or long-term (≥11 yr) follow-up after adjusting for baseline covariates (all, p > 0.05). Conclusion: A new diagnosis of VS frequently imparts significant anxiety on the patient and leads to a temporary reduction in QOL. Notably, anxiety domain QOL scores among patients with newly diagnosed VS are poorer than patients who have observed their tumor for 6 months or longer. When feasible, an initial period of observation may afford patients valuable time to reconcile with the new diagnosis, to learn more about treatment options, and to discover whether there is tumor growth. In turn, this valuable information can be used to inform sound decision-making regarding tumor management.

AbstractObjectiveAcute myeloid leukemia (AML) can be subtyped based on recurrent cytogenetic and molecular genetic abnormalities with diagnostic and prognostic significance. Although cytogenetic characterization classically involves conventional chromosome and/or fluorescence in situ hybridization (FISH) assays, limitations of these techniques include poor resolution and the inability to precisely identify breakpoints.MethodWe evaluated whether an NGS‐based methodology that detects structural abnormalities and copy number changes using mate pair sequencing (MPseq) can enhance the diagnostic yield for patients with AML.ResultsUsing 68 known abnormal and 20 karyotypically normal AML samples, each recurrent primary AML‐specific abnormality previously identified in the abnormal samples was confirmed using MPseq. Importantly, in eight cases with abnormalities that could not be resolved by conventional cytogenetic studies, MPseq was utilized to molecularly define eight recurrent AML‐fusion events. In addition, MPseq uncovered two cryptic abnormalities that were missed by conventional cytogenetic studies. Thus, MPseq improved the diagnostic yield in the detection of AML‐specific structural rearrangements in 10/88 (11%) of cases analyzed.ConclusionUtilization of MPseq represents a precise, molecular‐based technique that can be used as an alternative to conventional cytogenetic studies for newly diagnosed AML patients with the potential to revolutionize the diagnosis of hematologic malignancies.

Introduction: Dobutamine stress echocardiography (DSE) is frequently used to screen for obstructive coronary artery disease in the pre-liver transplant evaluation. Although atropine is a commonly used adjunctive medication, no study has evaluated its side effect profile in patients with end-stage liver disease (ESLD). Research Question: What is the safety of atropine in candidates undergoing pre-liver transplant evaluation when atropine is used in stress testing? Design: This multicenter, prospective study enrolled patients over a 6-month period undergoing pre-liver transplant evaluation. Each patient completed a questionnaire assessing anticholinergic-related symptoms within 24 hours of testing and 48 hours following. Comparisons were made among patients receiving any atropine dose versus those who did not and among patients receiving at least 1 mg atropine and those receiving less/none. Results: Forty patients were evaluated, and 32 (80%) had adjunctive atropine administered. No differences in clinical characteristics were noted. In comparisons among patients receiving any dose of atropine with those who did not, questionnaire results indicated a higher rate of nausea prior to testing and higher overall symptom severity following testing in patients not receiving atropine. In comparisons among patients receiving less than 1 mg atropine with those receiving at least 1 mg atropine, no difference in pre- or posttesting questionnaire responses was present. No patient in the study required reversal agents or hospitalization within 7 days of testing. Conclusions: Atropine, a hepatically metabolized medication, did not predispose patients with ESLD to an increased symptom burden, and clinical outcomes related to DSE were unaffected.

Objectives: To highlight superior semicircular canal dehiscence (SSCD) involving the superior petrosal sinus (SPS), and to propose a novel classification system for SPS associated SSCD with potential surgical implications. Study Design: Multicenter retrospective review. Setting: Three tertiary referral centers. Patients: All patients diagnosed with SPS associated SSCD (1/2000 to 8/2016). Radiographic findings and clinical symptoms were analyzed. Intervention: Surgical repair or observation. Main Outcome Measure: Radiographic findings and clinical symptoms were analyzed. Results: Thirty-three dehiscences (30 patients) involving the SPS were identified. The average age at the time of presentation was 52.5 years (median, 56.9; range, 4.9–75.3 yr), and 53.3% of patients were men. Three patients had bilateral SPS associated SSCD. The most common associated symptoms at presentation were episodic vertigo (63.6%), subjective hearing loss (60.6%), and aural fullness (57.6%). Four distinct types of dehiscence were identified: class Ia. SSCD involving a single dehiscence into an otherwise normal appearing SPS; class Ib. SSCD involving a single dehiscence into an apparent venous anomaly of the SPS; class IIa. SSCD involving two distinct dehiscences into the middle cranial fossa and the SPS; class IIb. SSCD involving a single confluent dehiscence into the middle cranial fossa and the SPS. Conclusions: SSCD involving the SPS represents a small but distinct subset of SSCD cases. This scenario can create a unique set of symptoms and surgical challenges when intervention is sought. Clinical findings and considerations for surgical intervention are provided to facilitate effective diagnosis and management.

TPS2618 Background: Tipifarnib is a potent and highly selective inhibitor of farnesyltransferase (FT). FT catalyzes the post-translational attachment of farnesyl groups to signaling proteins that are requisite for localization to the inner cell membrane. While all RAS isoforms (KRAS/NRAS/HRAS) are FT substrates, only HRAS is exclusively dependent upon farnesylation for membrane localization and signaling activation, making HRAS mutant tumors uniquely susceptible to tipifarnib mediated inhibition of FT. Tipifarnib has demonstrated robust activity in HRAS mutant head and neck squamous cell carcinoma (HNSCC) and HRAS mutant squamous non-small cell lung cancer (NSCLC) patient derived xenograft (PDX) models resistant to standard therapies. Methods: This is a multi-institutional, open-label Phase II trial evaluating the efficacy and safety of tipifarnib for pts with HRAS mutant solid tumors. Pts must have either unresectable, locally advanced or metastatic non-hematological malignancies that harbor a missense HRAS mutation. The primary endpoint of the study is overall response rate. Secondary endpoints include safety and tolerability, PFS, duration of response. Two cohorts (N = 18 each) are enrolling, each being evaluated with a Simon two-stage design. Cohort 1 is for patients with malignant thyroid tumors of any histology. Cohort 2 was originally designated for pts with any other solid tumor. The prespecified activity goal for the first stage of accrual in Cohort 2 was met. Based on data observed in the first stage of this group, enrollment to the second stage of Cohort 2 has been limited to HRAS mutant HNSCC since August 2016. Enrolled patients are treated with tipifarnib 900 mg administered orally twice daily on days 1-7 and 15-21 of 28-day treatment cycles until progression of disease or unacceptable toxicity. Clinical trial information: NCT02383927.

e12064 Background: Data on long-term cardiovascular effects and safety of aromatase inhibitors (AI) are limited and conflicting. The purpose of the current study was to evaluate the effect of AI on vascular injury as assessed by peripheral endothelial function among women with breast cancer. Methods: This is an observational, prospective study of 96 postmenopausal women with breast cancer at initiation of treatment, with or without AI. All participants underwent baseline and 6-12 months follow up non-invasive peripheral endothelial function measurement. Reactive hyperemia index (RHI) was measured using the EndoPAT test. The primary endpoint was endothelial function deterioration of at least 20% between baseline and follow-up. Results: Mean age of the study population was 66±7 years. There was no statistical difference in demographic data between the groups. Compared with the control group, more women in the treatment group demonstrated worsening of RHI (53% vs. 42%, p = 0.207) between baseline and 6-12 month follow up measurement. There was no statistical difference between the groups at baseline. When RHI deterioration was evaluated as a dichotomous variable, with a 20% cutoff, women in the AI group demonstrated higher rates of RHI deterioration (28% vs. 8%, p=0.020). The risk of AIs for endothelial dysfunction was correlated with burden of cardiovascular (CV) risk, such that in women with >3 CV risk factors, AIs were associated with increased risk of RHI deterioration (42% vs. 10%, p=0.016), whereas in women with <2 CV risk factors, rates of RHI deterioration were similar in AI and control groups (20% vs. 7%, p = 0.232). Conclusions: This study suggests that AI therapy may be associated with vascular injury as detected by deterioration in endothelial function. The effect is more pronounced among women with higher baseline CV risk factor burden. The results of this study have potentially important implications for patients with breast cancer being treated with AI and for women at increased lifetime risk of breast cancer who may use AI for breast cancer risk reduction. Clinical trial information: NCT00719966.

9517 Background: Although PD-1/L1 axis directed therapies induce durable responses in some mm patients (pts), biomarkers of response remain elusive. We hypothesized that quantifying key immune suppression mechanisms within the tumor microenvironment would provide superior predictors of response to anti-PD-1 compared with single marker assessment. Methods: Pre-treatment tumor biopsies from 124 mm pts treated with anti-PD-1 at 7 academic centers were fluorescently stained with multiple immune markers in discovery (n = 24) and validation (n = 100) cohorts. Selected biomarker signatures, PD-1/PD-L1 interaction score (proportion of PD-1+ cells co-localized with PD-L1) and IDO1/HLA-DR co-expression were evaluated for anti-PD-1 treatment response and survival. Slides were imaged using Vectra; biomarker positive cells and their co-localization were objectively quantified in pathologist-selected regions using novel Automated Quantitative Analysis (AQUA) algorithms. Results: In the discovery cohort, high levels of PD-1/PD-L1 interaction score and/or IDO1/HLA-DR coexpression was strongly positively associated with response to anti-PD-1 (p = 0.0005). In contrast, other individual biomarkers (PD-1, PD-L1, CD8) were not associated with response or survival (p > 0.10). This finding was replicated in the validation cohort: pts with high PD-1/PD-L1 and/or IDO1/HLA-DR were more likely to respond to treatment (p = 0.009). These pts also experienced a three-fold increase in progression free survival (hazards ratio (HR) = 0.33; p = 0.003) and overall survival (HR = 0.34; p = 0.004). Multivariate analyses revealed that these findings were independent of BRAF mutation, stage, LDH and prior therapy. In the combined cohort (n = 124), 80% of responding pts had higher levels of PD-1/PD-L1 interaction scores and/or IDO1/HLA-DR. In contrast, PD-L1 expression alone (≥1% or ≥50%) was not predictive of PFS or OS (p > 0.1). Conclusions: This novel multiplexed method profiling key tumor-immune suppression pathways identified mm pts likely to respond to anti-PD-1 therapy. This method could help stratify patients for PD-1 monotherapy and be useful in guiding future clinical trials.