Citations

BACKGROUND: Patients with inflammatory bowel disease (IBD), particularly ulcerative colitis (UC), have a higher risk of Clostridium difficile infection (CDI) than the general population (1). The incidence of CDI is increasing among patients with IBD, and certain UC treatments may be associated with greater risk (1). We report CDI events in the tofacitinib UC clinical program, and the incidence of CDI among patients receiving other treatments for UC. METHODS: For the tofacitinib UC program, rates of CDI (patients with an adverse event [AE] of CDI, Clostridium difficile colitis, or Clostridium test-positive, plus concomitant oral metronidazole or vancomycin, counted once per cohort) are reported for Induction Cohort (patients from an 8-week Phase [P]2 and two 8-week P3 induction studies; placebo or tofacitinib 10 mg twice daily [BID; NCT00787202; NCT01465763; NCT01458951]); Maintenance Cohort (patients from a 52-week maintenance study; placebo or tofacitinib 5 or 10 mg BID [NCT01458574]); and Overall Cohort (all tofacitinib-treated patients in P2/3 induction and maintenance studies and an ongoing, open-label, long-term extension study [as of December 2016; NCT01470612]). Positive Clostridium difficile test at screening was an exclusion criterion for program entry. Overall Cohort incidence rate (IR) was calculated as number of unique patients with events per 100 patient-years (PY). For contextualization, CDI rates among patients receiving other UC medications were obtained from a retrospective cohort study utilizing data from the Truven MarketScan ® Database, an administrative healthcare claims database in the US. Patients with moderately to severely active UC, with either an inpatient or outpatient diagnosis code of CDI, plus a prescription for oral therapy (including metronidazole, vancomycin, and fidaxomicin) within 14 days of CDI diagnosis (observation period: October 1, 2010–September 30, 2015), were included. Truven cohort IRs were calculated as number of patients with events per 100 PY. RESULTS: In the tofacitinib Induction Cohort, CDI occurred in 3 patients (placebo, 1/282 [0.4%]; tofacitinib 10 mg BID, 2/938 [0.2%]). In the Maintenance Cohort, CDI occurred in 3 patients (placebo, 3/198 [1.5%]; tofacitinib 5 or 10 mg BID, 0/394 [0.0%]). In the Overall Cohort of all tofacitinib-treated patients (1,664 PY of follow-up), CDI occurred in 8/1,157 patients (0.7%), with an IR (95% confidence interval [CI]) of 0.48 (0.21, 0.95). Two cases were reported as serious AEs. All were mild (n = 4) or moderate (n = 4) in severity; 6 continued with study treatment, one temporarily discontinued, one permanently discontinued. All CDI cases resolved with treatment. In the Truven Cohort, 160 CDI events occurred during 4,918 PY of follow-up, with an overall CDI IR (95% CI) of 3.25 (2.77, 3.80); of which 116 were CDI-associated hospitalizations (4,936 PY of follow-up). Among patients receiving azathioprine, 6-mercaptopurine, or tumor necrosis factor inhibitors, CDI IRs were 3.23 (2.18, 4.62), 2.31 (1.26, 3.87), and 3.58 (2.95, 4.29), respectively. CONCLUSION(S): In the tofacitinib UC program, CDI rates among patients receiving tofacitinib were similar to or lower than those observed with placebo. The IR among patients receiving tofacitinib was numerically lower than those observed for immunomodulators and tumor necrosis factor inhibitors in the Truven Cohort.

Background Preliminary clinical studies on the safety and efficacy of the pipeline embolization device (PED) for the treatment of small/medium aneurysms have demonstrated high occlusion rates with low complications. Objective To evaluate the safety and effectiveness of the PED for treatment of wide necked small and medium intracranial aneurysms. Methods PREMIER is a prospective, multicenter, single arm trial. Patients were treated with the PED for unruptured wide necked aneurysms, measuring ≤12 mm along the internal carotid artery or vertebral artery, between July 2014 and November 2015. At 1 year post-procedure, the primary effectiveness endpoint was complete occlusion (Raymond grade 1) without major parent vessel stenosis (≤50%) or retreatment, and the primary safety endpoint was major stroke in the territory supplied by the treated artery or neurologic death. Results A total of 141 patients were treated with PEDs (mean age 54.6±11.3 years, 87.9% (124/141) women). Mean aneurysm size was 5.0±1.92 mm, and 84.4% (119/141) measured <7 mm. PED placement was successful in 99.3% (140/141) of patients. Mean number of PEDs implanted per patient was 1.1±0.26; a single PED was used in 92.9% (131/141) of patients. At 1 year, 97.9% (138/141) of patients underwent follow-up angiography with 76.8% (106/138) of patients having met the study’s primary effectiveness endpoint. The combined major morbidity and mortality rate was 2.1% (3/140). Conclusions Treatment of wide necked small/medium aneurysms with the PED results in high rates of complete occlusion without significant parent vessel stenosis and low rates of permanent neurologic complications. Trial registration NCT02186561 .

OBJECTIVENonhome discharge and unplanned readmissions represent important cost drivers following spinal fusion. The authors sought to utilize different machine learning algorithms to predict discharge to rehabilitation and unplanned readmissions in patients receiving spinal fusion.METHODSThe authors queried the 2012–2013 American College of Surgeons National Surgical Quality Improvement Program (ACS-NSQIP) for patients undergoing cervical or lumbar spinal fusion. Outcomes assessed included discharge to nonhome facility and unplanned readmissions within 30 days after surgery. A total of 7 machine learning algorithms were evaluated. Predictive hierarchical clustering of procedure codes was used to increase model performance. Model performance was evaluated using overall accuracy and area under the receiver operating characteristic curve (AUC), as well as sensitivity, specificity, and positive and negative predictive values. These performance metrics were computed for both the imputed and unimputed (missing values dropped) datasets.RESULTSA total of 59,145 spinal fusion cases were analyzed. The incidence rates of discharge to nonhome facility and 30-day unplanned readmission were 12.6% and 4.5%, respectively. All classification algorithms showed excellent discrimination (AUC > 0.80, range 0.85–0.87) for predicting nonhome discharge. The generalized linear model showed comparable performance to other machine learning algorithms. By comparison, all models showed poorer predictive performance for unplanned readmission, with AUC ranging between 0.63 and 0.66. Better predictive performance was noted with models using imputed data.CONCLUSIONSIn an analysis of patients undergoing spinal fusion, multiple machine learning algorithms were found to reliably predict nonhome discharge with modest performance noted for unplanned readmissions. These results provide early evidence regarding the feasibility of modern machine learning classifiers in predicting these outcomes and serve as possible clinical decision support tools to facilitate shared decision making.

Innate immune sensing is essential for the proinflammatory program in cellular senescence.

6010 Background: An evolutionary action scoring algorithm (EAp53) based on phylogenetic sequence variations and speciation stratifies head and neck squamous cell carcinoma (HNSCC) patients bearing TP53 missense mutations as high-risk (high, EAp53≥75), associated with poor outcomes, or low-risk (low), with similar outcomes as TP53 wild-type (wt), and has been validated as a reliable prognostic marker. This study is designed to further validate prior findings that EAp53 is a prognostic marker for locally advanced HNSCC patients, and assess its predictive value for treatment outcomes to adjuvant bio-chemoradiotherapy. Methods: Eighty one resection specimens from patients treated surgically for stage III or IV human papillomavirus-negative (HPV(-)) HNSCC with high-risk pathologic features, who received either Arm 1) radiotherapy(RT)+cetuximab(CTX)+cisplatin or Arm 2) RT+CTX+docetaxel, as adjuvant treatment in a phase II randomized clinical trial (RTOG 0234) underwent TP53 targeted sequencing, and EAp53 scoring. The EAp53 scores were correlated with clinical outcomes. Due to limited sample sizes, patients were combined into 2 EAp53 groups: wt/low and high/other. Results: At median follow-up of 10 years, there was a significant interaction between treatment and EAp53 group for overall survival (OS) (p = 0.008), disease-free survival (DFS) (p = 0.05) and distant metastasis (DM) (p = 0.004). Within arm 2, high/other showed worse OS [HR 4.69 (1.52-14.50)], DFS [HR 2.69 (1.16-6.21)], and had higher DM [HR 11.71 (1.50-91.68)] than wt/low. Within arm 1, there was no significant difference by EAp53 in OS, DFS and DM. Within the wt/low group, arm 2 had better OS [HR 0.11 (0.03-0.36)], DFS [HR 0.24 (0.09-0.61)], and DM [HR 0.04 (0.01-0.31)] than arm 1 but this was not found in high/other. Conclusions: High/other EAp53 scores were associated with worse survival for patients in arm 2. Arm 2 is associated with better survival than arm 1 for patients with wt/low EAp53. This benefit appears to be largely driven by a reduction in DM. Further validation is required to determine whether EAp53 can be used for personalized post-operative treatment decisions in HPV(-) HNSCC.

5078 Background: Strategies integrating androgen targeted and locoregional therapies are being increasingly used in PCa with regional spread, but are rarely curative. Angiogenesis inhibitors delay progression in castration resistant PCa and may synergize with ADT through endothelial cell apoptosis in hormone naïve patients (pts). We hypothesized that the frontline combination of ADT with the potent VEGF inhibitor Axi would improve PCa control relative to ADT alone and allow for meaningful time off systemic therapy after surgical consolidation. Methods: Pts with either clinically detected LN+ (TxN1M0 or TxNxM1a) or very high risk for LN PCa were treated with ADT for 2 mos and then randomized 2:1 to respectively add open label Axi (5 mg PO bid) vs. continue ADT alone for 4 mos until surgery. Those responding with PSA ≤5 ng/mL were offered prostatectomy and extended pelvic lymphadenectomy (RP). ADT +/- Axi was withheld postoperatively and PSA measured q3 mos until 1 y. Primary objective: proportion of pts progression free (FFP) 12 mos after RP, defined as PSA ≤1.0 ng/mL and no radiation or ADT, aiming to detect a 35% difference favoring ADT+Axi. Results: 72 pts completed accrual. We report on the 54 pts with LN+ disease: median age 62 y (range 42-76), pretreatment PSA 22.9 ng/mL (range 3.6 - 404.4), 38 N1 / 16 M1a. Table shows presurgical therapy outcomes. Path responses in the prostate were similar between arms, but in 5 ADT+Axi vs. 0 ADT LN+ pts there was no residual nodal disease. Testosterone recovery: 24/26 ADT+Axi and 9/9 ADT RP pts by 6 mos. 21/36 ADT+Axi and 15/18 ADT pts have failed; 1 y FFP estimates 48.0% (SE 8.6%) and 16.7% (SE 8.3%), respectively (p = 0.02). 1 y undetectable PSA 9 pts (6 ADT+Axi). No grade 4 toxicities or unexpected side-effects were observed. Conclusions: 1 year after RP, ADT+Axi resulted in proportionally greater number of LN+ PCa pts off treatment and progression free than ADT alone. Tissue analysis is evaluating predictors of benefit to further develop angiogenesis inhibition as part of combination strategies for hormone naïve PCa. Clinical trial information: NCT01409200. [Table: see text]