Citations

Introduction: The impact of beta blocker use on surgical outcomes of cancer patients receiving immunotherapy is unknown. Hypothesis: Beta blocker use is associated with lower post-operative mortality in cancer patients on immunotherapy. Methods: We used an institutional Advanced Cohort Explorer to identify all patients who underwent any surgical procedure less than 90 days after receiving immunotherapy. Data on the procedure performed as well as the post-operative outcome were collected and analyzed per the pre-operative beta blocker use status. Results: A total of 233 patients underwent surgery between 09/2011-06/2019. Mean age was 64.7 years (range: 16-92). The most common cancer diagnoses were lung (48, 44.4%), melanoma (49, 45.4%) and kidney (11, 10.2%). Immunotherapy medications were pembrolizumab ( 127, 54.5%), nivolumab (51, 21.9%), ipilimumab (43, 18.5%), atezolizumab (11, 4.7%) and avelumab (1, 0.43%). Pre-operative beta blocker use was documented in 140 (60.1%) patients. Most common surgical procedures were skin resection (75, 32.1%), wound repair (47, 20.2%), vascular procedures (36, 15.5%), urethral procedures 16 (6.9%) and sentinel lymph node biopsies (10, 4.3%). The 30-day mortality rate was 10.3% (24 deaths). In a multi-variable logistic regression analysis, pre-operative use of beta blockers was associated with a lower risk of death within 30 days from surgery (OR 0.34, CI 0.13-0.87, P=0.024). 30-day mortality rates were higher in patients undergoing vascular (50%, 17 of 34) versus non-vascular (3.5%, 7 of 199) procedures (P<0.0001) in a Chi Square test. Conclusions: Beta blocker use is associated with a lower 30-day mortality rate after surgical procedures in cancer patients treated with immunotherapy. Further investigation is warranted.

Abstract Chromosome region maintenance protein 1 (CRM1) mediates protein export from the nucleus and is a new target for anticancer therapeutics. Broader application of KPT-330 (selinexor), a first-in-class CRM1 inhibitor recently approved for relapsed multiple myeloma and diffuse large B-cell lymphoma, have been limited by substantial toxicity. We discovered that salicylates markedly enhance the antitumor activity of CRM1 inhibitors by extending the mechanisms of action beyond CRM1 inhibition. Using salicylates in combination enables targeting of a range of blood cancers with a much lower dose of selinexor, thereby potentially mitigating prohibitive clinical adverse effects. Choline salicylate (CS) with low-dose KPT-330 (K+CS) had potent, broad activity across high-risk hematological malignancies and solid-organ cancers ex vivo and in vivo. The K+CS combination was not toxic to nonmalignant cells as compared with malignant cells and was safe without inducing toxicity to normal organs in mice. Mechanistically, compared with KPT-330 alone, K+CS suppresses the expression of CRM1, Rad51, and thymidylate synthase proteins, leading to more efficient inhibition of CRM1-mediated nuclear export, impairment of DNA-damage repair, reduced pyrimidine synthesis, cell-cycle arrest in S-phase, and cell apoptosis. Moreover, the addition of poly (ADP-ribose) polymerase inhibitors further potentiates the K+CS antitumor effect. K+CS represents a new class of therapy for multiple types of blood cancers and will stimulate future investigations to exploit DNA-damage repair and nucleocytoplasmic transport for cancer therapy in general.

Abstract Endocrine therapy is underutilized to reduce breast cancer incidence among women at increased risk. Polygenic risk scores (PRSs) assessing 77 breast cancer genetic susceptibility loci personalizes risk estimates. We examined effect of personalized PRS breast cancer risk prediction on intention to take and endocrine therapy uptake among women at increased risk. Eligible participants had a 10-year breast cancer risk ≥5% by Tyrer–Cuzick model [International Breast Cancer Intervention Study (IBIS)] or ≥3.0 % 5-year Gail Model risk with no breast cancer history or hereditary breast cancer syndrome. Breast cancer risk was estimated, endocrine therapy options were discussed, and endocrine therapy intent was assessed at baseline. After genotyping, PRS-updated breast cancer risk estimates, endocrine therapy options, and intent to take endocrine therapy were reassessed; endocrine therapy uptake was assessed during follow-up. From March 2016 to October 2017, 151 patients were enrolled [median (range) age, 56.1 (36.0–76.4 years)]. Median 10-year and lifetime IBIS risks were 7.9% and 25.3%. Inclusion of PRS increased lifetime IBIS breast cancer risk estimates for 81 patients (53.6%) and reduced risk for 70 (46.4%). Of participants with increased breast cancer risk by PRS, 39 (41.9%) had greater intent to take endocrine therapy; of those with decreased breast cancer risk by PRS, 28 (46.7%) had less intent to take endocrine therapy (P &lt; 0.001). On multivariable regression, increased breast cancer risk by PRS was associated with greater intent to take endocrine therapy (P &lt; 0.001). Endocrine therapy uptake was greater among participants with increased breast cancer risk by PRS (53.4%) than with decreased risk (20.9%; P &lt; 0.001). PRS testing influenced intent to take and endocrine therapy uptake. Assessing PRS effect on endocrine therapy adherence is needed. Prevention Relevance: Counseling women at increased breast cancer risk using polygenic risk score (PRS) risk estimates can significantly impact preventive endocrine therapy uptake. Further development of PRS testing to personalize breast cancer risk assessments and endocrine therapy counselling may serve to potentially reduce the incidence of breast cancer in the future.

INTRODUCTION: Ablation of Barrett's esophagus (BE) is the preferred approach for the treatment of neoplasia without visible lesions. Limited data on cryoballoon ablation (CBA) suggest its potential clinical utility. We evaluated the safety and efficacy of CBA in a multicenter study of patients with neoplastic BE. METHODS: In a prospective clinical trial, 11 academic and community centers recruited consecutive patients with BE of 1–6 cm length and low-grade dysplasia, high-grade dysplasia (HGD), or intramucosal adenocarcinoma (ImCA) confirmed by central pathology. Patients with symptomatic pre-existing strictures or visible BE lesions had dilation or endoscopic mucosal resection (EMR), respectively, before enrollment. A nitrous oxide cryoballoon focal ablation system was used to treat all visible columnar mucosa in up to 5 sessions. Study end points included complete eradication of all dysplasia (CE-D) and intestinal metaplasia (CE-IM) at 1 year. RESULTS: One hundred twenty patients with BE with ImCA (20%), HGD (56%), or low-grade dysplasia (23%) were enrolled. In the intention-to-treat analysis, the CE-D and CE-IM rates were 76% and 72%, respectively. In the per-protocol analysis (94 patients), the CE-D and CE-IM rates were 97% and 91%, respectively. Postablation pain was mild and short lived. Fifteen subjects (12.5%) developed strictures requiring dilation. One patient (0.8%) with HGD progressed to ImCA, which was successfully treated with EMR. Another patient (0.8%) developed gastrointestinal bleeding associated with clopidogrel use. One patient (0.8%) had buried BE with HGD in 1 biopsy, not confirmed by subsequent EMR. DISCUSSION: In patients with neoplastic BE, CBA was safe and effective. Head-to-head comparisons between CBA and other ablation modalities are warranted (clinicaltrials.gov registration NCT02514525).

Purpose To assess if the choice of acetaminophen formulation (intravenous vs oral) when administered preoperatively for ambulatory cystoscopy procedures is associated with differences in anesthetic outcomes. Methods Medical records of adult patients undergoing ambulatory cystoscopy procedures at an outpatient procedural center from July 1, 2014, through November 30, 2017, were abstracted. The association between anesthetic outcomes (severe pain, rescue opioids, postoperative nausea, and vomiting) and acetaminophen formulation was assessed. Propensity-adjusted analyses were performed using inverse probability of treatment weighting to account for potential confounders. Results During the study time frame, there were 611 intravenous and 2955 oral acetaminophen administrations for cystoscopy procedures. Postoperative bladder spasms were a major contributor to severe pain and complicated 1036 cases, with similar rates between intravenous (N = 183, 29.9%) and oral (N = 853, 28.9%) formulations, P = .625. After adjusting for bladder spasms, intravenous acetaminophen was associated with longer anesthesia recovery (estimate 5.2 [95% CI 0.5-9.9] minutes, P = .030), use of rescue opioids (odds ratio 1.33 [1.07-1.66], P = .012), and postoperative nausea and vomiting (1.40 [1.02-1.93], P = .037), but not severe pain (1.07 [0.81-1.40], P = .640). Conclusion Preoperative intravenous acetaminophen compared to oral acetaminophen for ambulatory cystoscopy procedures was not associated with better anesthetic outcomes. Bladder spasms were a major contributor to postoperative pain.

8106 Background: Bcl-2 family proteins are expressed in SCLC and are associated with chemotherapy resistance. AT-101 is an oral, pan Bcl-2 family protein inhibitor (Bcl-2, Bcl-XL, Mcl-1, and Bcl-w) and potent inducer of proapoptotic proteins. AT-101 has demonstrated activity in SCLC models, including those that express Mcl-1 and are resistant to other Bcl-2 inhibitors. The P1 portion of the study was previously reported. Methods: Pts ≥18 years of age, PS 0–1, with relapsed or refractory SCLC after first line chemotherapy with measurable disease per RECIST were eligible. Pts were stratified into 2 cohorts; cohort A ≥ 60 days and cohort B < 60 days relapse from prior chemotherapy and treated with T 1.25 mg/m2 daily and AT-101 40 mgs daily on days 1–5, q21 along with the use of myeloid growth factors. Adverse Events (AEs) were graded by the NCI CTCAE v. 3.0. Efficacy assessments (RECIST) were performed every 6-weeks. A 2-stage design was used with power/alpha of 80%/0.05 to detect a RR of > 25% and > 5%, in cohort A and B respectively. Results: 36 pts enrolled: ages 41–76; cohort A/B 23/13. The PR/SD/PD/NE rates were 17%/70%/9%/4% and 8%/54%/23%/15%, in cohorts A/B respectively. The median times to progression (TTP) were 18 and 13 weeks, respectively. The most common (>20 %) AEs (all grades): anemia (64%); neutropenia (53%); nausea (47%); fatigue (44%); thrombocytopenia (42%); dyspnoea (25%); and vomiting (22%). Most common Grade 3/4 related events (>5%): neutropenia (31%); thrombocytopenia (25%); anemia (14%); and asthenia (6%). No ileus was reported. Conclusions: AT-101 can be safely combined with T. The observed toxicities were consistent with the known rates of G4 cytopenias of T alone. The response rates observed did not meet the criteria for additional enrolment; however, many patients had a best response of SD and the median TTP in both cohorts was favorable compared to historical controls. Additional trials of AT-101 in SCLC are ongoing. [Table: see text]