Citations

Background: Antibiotic use may increase hospital length of stay (LOS) among older patients with advanced cancer who are transitioned to comfort measures. Methods: We studied a cohort of patients with advanced cancer aged ≥65 years who were transitioned to comfort measures during admission from July 1, 2014, through November 30, 2016. We evaluated the association between antibiotic exposure and LOS using a Poisson regression model adjusted for age, gender, cancer type, comorbidities, infection, and intensive care unit admission. Results: Among 461 patients with advanced cancer, median age was 74 years (range: 65-99), 49.0% (n = 226) were female, and 20.6% (n = 95) had liquid tumors. Overall, 82.9% (n = 382) received ≥1 antibiotic and 64.6% (n = 298) had ≥1 infection diagnosis during hospitalization. Infection diagnoses commonly included sepsis (35%, n = 161/461), pneumonia (25%, n = 117/461), and urinary tract infection (14%, n = 66/461). Among those receiving antibiotics, the most common choices included vancomycin (79%, n = 300/382), cephalosporins (63%, n = 241/382), and penicillins (45%, n = 172/382). In a multivariable Poisson regression model, LOS was 34% longer (count ratio = 1.34, [95% confidence interval: 1.20-1.51]) among those exposed versus unexposed to antibiotics. Conclusions: Antibiotic use among patients with advanced cancer who are transitioned to comfort measures is associated with longer LOS. These data illustrate the importance of tradeoffs associated with antibiotic use, such as unintended increased LOS, when striving for goal-concordant care near the end of life.

Abstract Knowledge of the molecular interactions of biological and chemical entities and their involvement in biological processes or clinical phenotypes is important for data interpretation. Unfortunately, this knowledge is mostly embedded in the literature in such a way that it is unavailable for automated data analysis procedures. Biological expression language (BEL) is a syntax representation allowing for the structured representation of a broad range of biological relationships. It is used in various situations to extract such knowledge and transform it into BEL networks. To support the tedious and time-intensive extraction work of curators with automated methods, we developed the BEL track within the framework of BioCreative Challenges. Within the BEL track, we provide training data and an evaluation environment to encourage the text mining community to tackle the automatic extraction of complex BEL relationships. In 2017 BioCreative VI, the 2015 BEL track was repeated with new test data. Although only minor improvements in text snippet retrieval for given statements were achieved during this second BEL task iteration, a significant increase of BEL statement extraction performance from provided sentences could be seen. The best performing system reached a 32% F-score for the extraction of complete BEL statements and with the given named entities this increased to 49%. This time, besides rule-based systems, new methods involving hierarchical sequence labeling and neural networks were applied for BEL statement extraction.

Postsurgical gastric dysfunction is common, but the mechanisms are varied and poorly understood. The pylorus normally acts as an electrical barrier isolating gastric and intestinal slow waves. In this report, we present an aberrant electrical conduction pathway arising between the stomach and small intestine, following pyloric excision and surgical anastomosis, as a novel disease mechanism. A patient was referred with postsurgical gastroparesis following antrectomy, gastroduodenostomy, and vagotomy for peptic ulceration. Scintigraphy confirmed markedly abnormal 4-h gastric retention. Symptoms included nausea, vomiting, postprandial distress, and reflux. Intraoperative, high-resolution electrical mapping was performed across the anastomosis immediately before revision gastrectomy, and the resected anastomosis underwent immunohistochemistry for interstitial cells of Cajal. Mapping revealed continuous, stable abnormal retrograde slow-wave propagation through the anastomosis, with slow conduction occurring at the scar (4.0 ± 0.1 cycles/min; 2.5 ± 0.6 mm/s; 0.26 ± 0.15 mV). Stable abnormal retrograde propagation continued into the gastric corpus with tachygastria (3.9 ± 0.2 cycles/min; 1.6 ± 0.5 mm/s; 0.19 ± 0.12 mV). Histology confirmed ingrowth of atypical ICC through the scar, defining an aberrant pathway enabling transanastomotic electrical conduction. In conclusion, a “gastrointestinal aberrant pathway” is presented as a novel proposed cause of postsurgical gastric dysfunction. The importance of aberrant anastomotic conduction in acute and long-term surgical recovery warrants further investigation. NEW & NOTEWORTHY High-resolution gastric electrical mapping was performed during revisional surgery in a patient with severe gastric dysfunction following antrectomy and gastroduodenostomy. The results revealed continuous propagation of slow waves from the duodenum to the stomach, through the old anastomotic scar, and resulting in retrograde-propagating tachygastria. Histology showed atypical interstitial cells of Cajal growth through the anastomotic scar. Based on these results, we propose a “gastrointestinal aberrant pathway” as a mechanism for postsurgical gastric dysfunction.

e18261 Background: Multidisciplinary tumor board meetings have shown to improve quality and outcome in the care of cancer patients. Many tertiary centers conduct site specific tumor board meetings but not all the centers especially community oncology and international centers have the manpower capacity to hold site specific meetings, the overall impact of tumor boards on patients care may vary based on its structure and composition. We propose that institutional collaboration in the comprehensive care of cancer patients utilizing E-consult and E tumor board may help to improve patient care. Methods: Retrospective data of 134 patient cases seen at the American hospital Dubai between 2016-2018 was analyzed. Cases that were reviewed at the American Hospital multidisciplinary tumor board meeting (AHD-MDT) and also referred for second opinion utilizing Mayo e-consult/e-tumor board service were analyzed using electronic health record, AHD-MDT meeting minutes and reports of Mayo e-consult/e-tumor board. 3 major areas of case assessment for review were selected 1. Pathology . 2. Medical imaging. 3. Clinical recommendations. Variation in assessment and recommendations between AHD- MDT and Mayo Clinic were compared. Results: A total of 1018 cases were reviewed in the AHD-MDT between 2016 and 2018. 136 out of the 1018(13%) cases were referred for second opinion utilizing Mayo E-Consult or E-tumor board service. 117 cases were included in the analysis as there was missing data in 4 patients, 9 were duplicate and 4 were cancelled and 7 cases were not reviewed at AHD-MDT. In 78 cases pathology was reviewed at Mayo but 4 (5%) were not reviewed at AHD. In 74 (95%) cases, pathology was reviewed both at AHD and Mayo. There was change (Ch) in 2 (3%), 7(9%)updated(Ud) and no change(Ch) in 65 cases(88%). 97 cases of imaging had change(Ch) in 1 case (1%). 101 cases of e-consult/e-tumor board were assessed for clinical recommendations. There was change(Ch) in 3(3%), 2/3 cases had a change in plan due to change in the pathology. In 35(35%) the plan was updated (Ud) and 7 out of 35(20%) were due to updated(Ud) pathology. Conclusions: Our data indicates that international collaboration as part of MCCN has resulted in significant improvement in the patient care. In a select group of challenging cases, 35% had an improvement in the final treatment plan after utilization of e-consult/e-tumor board service.

5008 Background: Androgen receptor (AR) signaling is an important growth mechanism in mCRPC, providing the rationale for treatment with AR axis inhibitors such as ENZ and AAP. Targeting AR with anti-androgens such as ENZ can result in compensatory autocrine and paracrine androgenic stimulation. Therefore, using ENZ with the androgen biosynthesis inhibitor AAP to dampen these resistance mechanisms could improve clinical outcomes relative to ENZ alone. Methods: Men with progressive mCRPC by Prostate Cancer Working Group 2 criteria were eligible. Prior treatment with taxanes for mCRPC and any prior treatment with ENZ or AAP was exclusionary. Patients (pts) were randomized 1:1 to ENZ or ENZ/AAP at standard FDA-approved doses. Randomization was stratified by prior chemotherapy and Halabi prognostic three risk groups. Castrating therapy was maintained. The primary endpoint was overall survival (OS) defined as the date of randomization from date of death or last follow-up. The log-rank test had 90% power to detect a hazard ratio for OS of 0.77 with a one-sided type I error rate of 0.025. Secondary endpoints included radiographic progression free survival (rPFS) and on-treatment PSA declines. Exploratory endpoints included imaging changes, and changes in serum biomarkers such as androgens, angiokines, and circulating microRNA and RNA. The primary analysis was based on the stratified log-rank test adjusting on the stratification factors. Results: Between January 2014 and August 2016, 1311 men were randomized: 657 to ENZ and 654 to ENZ/AAP. Groups were well balanced between arms, including stratification variables. 15.6% of pts were high risk, 35.3% intermediate, and 48.1% low. Median OS was 33.6 mo (95% CI 30.5-36.4) and 32.7 mo (29.9-35.4) respectively, two-sided p = 0.53. Fifty percent PSA decline rate was 80% vs. 76.5%. Grade 3-5 adverse events (AE) (all attributions) were 55.6% and 68.8% respectively. Treatment discontinuation due to AEs occurred in 5% and 12%, pt withdrawal in 5% and 13%, and progression or death in 57% and 48% of pts respectively. Conclusions: Addition of abiraterone acetate to enzalutamide did not prolong survival in men with mCRPC. The combination resulted in more AEs than enzalutamide alone. Support: U10CA180821, U10CA180882, U24CA196171; https://acknowledgments.alliancefound.org . Clinical trial information: NCT01949337.

4521 Background: The MTAP gene encodes an essential enzyme for the salvage pathway of nucleotide synthesis and is frequently deleted in UBC. Anti-folate agents such as pemetrexed can effectively inhibit the de novo pathway of nucleotide synthesis and as a result, create a synthetic lethality in MTAP deficient UBC. We hypothesize that MTAP gene loss correlates with enhanced response to pemetrexed in UBC. Methods: We investigated MTAP gene deletion rates in the TCGA database and determined MTAP protein loss rates by immunohistochemistry (IHC) using a UBC tissue microarray (TMA) from 151 patients (pts). We then performed in vitro and in vivo studies using MTAP proficient and MTAP deficient bladder cancer cell lines. At the clinical level, we performed a retrospective analysis based on MTAP status of pts treated with pemetrexed as 2nd line at our institution between 2014 and 2018. We are now enrolling pts in a single-arm, open-label, phase II clinical trial (NCT02693717) with pemetrexed in pts with MTAP deficient UBC. Results: Per our TCGA and TMA IHC analyses, MTAP deficiency rate was 25.9% and 27.8%, respectively. MTAP deficient UBC cell lines were at least 40 times more sensitive to pemetrexed than MTAP proficient lines. Knockdown of the MTAP gene increased apoptosis rate by pemetrexed from approximately 20% to 60%. Additionally, pemetrexed significantly inhibited the growth of MTAP deficient or knockdown xenograft tumors but not MTAP proficient tumors. Retrospective analysis of 12 pts using RECIST criteria indicated that all 4 MTAP deficient UBC pts responded to pemetrexed whereas only 1 of 8 (12.5%) MTAP proficient UBC pts responded. Of the 6 pts enrolled on the clinical trial, 3 (50%) had complete or partial response, 1 had stable disease, 1 was not evaluable and 1 had disease progression. Combined analysis of the entire experience demonstrates a higher response rate in MTAP deficient UBC (70%) as compared to MTAP proficient UBC (12.5%). Conclusions: Our preclinical and clinical data demonstrate that MTAP loss in UBC leads to a state of synthetic lethality when treated with pemetrexed and should be further investigated as a novel biomarker to predict response to anti-folate agents.

e12003 Background: Irinotecan liposome injection (nal-IRI) uses intraliposomal stabilisation technology to enable high drug load and in-vivo stability. This analysis characterizes the PK profile of nal-IRI in pts with mBC. Methods: The expansion of NCT01770353 enrolled 30 pts with mBC over three cohorts (Cohort 1: ER+ and/or PR+ BC [C-1]; Cohort 2: Triple Negative BC [C-2]; and Cohort 3: BC with active Brain Metastasis [C-3]). Key inclusion criteria: ECOG ≤1; adequate organ function; and >1 and ≤5 prior lines of cytotoxic therapy in metastatic setting. Most pts received nal-IRI 60 mg/m2 salt-based equivalent (50 mg/m2 free base equivalent [FBE]) or 80 mg/m2 (70 mg/m2 FBE) q2w by iv infusion, based on tolerance; 2 pts were treated at 40 mg/m2 (35 mg/m2 FBE). Plasma samples were collected over 360h across cycles 1, 2 &3, and analysed using LC-MS/MS for total irinotecan. Data were analysed by a non-compartmental approach using Phoenix Winnonlin, and were compared with values from studies in other tumor types. Results: 21 patients were evaluable for PK analysis (C-1, n=6; C-2, n=7; and C-3, n=8). No trend for accumulation was observed in cycle 2 or 3, when comparing total irinotecan Cmax & exposure (area under the curve at 168 h [AUC168]) versus cycle 1. At 40-80 mg/m2 (35-70 mg/m2 FBE), Cmax of irinotecan tended to increase proportionally with total dose, and was comparable to studies in other tumour types (see Table). Among 29 pts who received nal-IRI, partial response (per RECIST) was observed in 10 pts. The most related TEAEs (≥ 25%) were diarrhea, nausea, vomiting, hypokalaemia, decreased appetite and fatigue. Stable disease was observed in 5 pts. Conclusions: PK parameters in patients with mBC were comparable to historical studies in patients with other tumour types. The safety profile of nal-IRI monotherapy appeared consistent with gastrointestinal and blood disorders. [Table: see text]