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Summary Background Pembrolizumab (PD-1 inhibitor) and cetuximab (EGFR inhibitor) are active as single agents and in combination with cytotoxic chemotherapy for recurrent or metastatic head and neck squamous cell carcinoma (HNSCC). Given each drug's single agent activity and unique mechanism of action, we aimed to evaluate the anti-tumour activity of PD-1 blockade with EGFR inhibition in recurrent or metastatic HNSCC. Methods This study is an open-label, non-randomised, multi-arm, phase 2 trial done at four academic centres in the USA. Participants were required to have platinum-resistant or platinum-ineligible, recurrent or metastatic HNSCC, be at least 18 years old, have an Eastern Cooperative Oncology Group performance status 0–1, have measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, and to have received no previous immunotherapy or EGFR inhibition. All participants received pembrolizumab 200 mg intravenously every 3 weeks, combined with an initial loading dose of cetuximab 400 mg/m2 intravenously followed by 250 mg/m2 intravenously weekly (21 day cycle). The primary endpoint was overall response rate defined as the proportion of participants with a partial or complete responses (per RECIST version 1.1) by 6 months in the intention-to-treat population. The safety population included all participants who received at least one dose of pembrolizumab. Herein, the final analysis of cohort 1 (no previous PD-1, PD-L1, or EGFR inhibition for recurrent or metastatic HNSCC) is reported. Three additional cohorts (two for participants with a previous response to immunotherapy followed by relapse or progression, with or without previous cetuximab exposure, and one for cutaneous HNSCC) will be reported separately once fully accrued. This study is registered with ClinicalTrials.gov , NCT03082534 , and remains open as the three additional cohorts are actively accruing participants. Findings Between March 22, 2017, and July 16, 2019, 33 participants were enrolled to cohort 1. All 33 participants received at least one dose of pembrolizumab. Median follow-up duration was 7·3 months (IQR 3·9–10·9). By 6 months, the overall response rate was 45% (95% CI 28–62), with 15 of 33 participants achieving a partial response. The most common grade 3–4 treatment-related adverse event was oral mucositis (three [9%] of 33 participants), and serious treatment-related adverse events occurred in five (15%) participants. No treatment-related deaths occurred. Interpretation Pembrolizumab combined with cetuximab shows promising clinical activity for recurrent or metastatic HNSCC, and merits further investigation. Funding Merck Sharp & Dohme.

The impact of statins, angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers (ARBs) on coronavirus disease 2019 (COVID-19) severity and recovery is important given their high prevalence of use among individuals at risk for severe COVID-19. We studied the association between use of statin/angiotensin-converting enzyme inhibitors/ARB in the month before hospital admission, with risk of severe outcome, and with time to severe outcome or disease recovery, among patients hospitalized for COVID-19. We performed a retrospective single-center study of all patients hospitalized at University of California San Diego Health between February 10, 2020 and June 17, 2020 (n = 170 hospitalized for COVID-19, n = 5,281 COVID-negative controls). Logistic regression and competing risks analyses were used to investigate progression to severe disease (death or intensive care unit admission), and time to discharge without severe disease. Severe disease occurred in 53% of COVID-positive inpatients. Median time from hospitalization to severe disease was 2 days; median time to recovery was 7 days. Statin use prior to admission was associated with reduced risk of severe COVID-19 (adjusted OR 0.29, 95%CI 0.11 to 0.71, p < 0.01) and faster time to recovery among those without severe disease (adjusted HR for recovery 2.69, 95%CI 1.36 to 5.33, p < 0.01). The association between statin use and severe disease was smaller in the COVID-negative cohort (p for interaction = 0.07). There was potential evidence of faster time to recovery with ARB use (adjusted HR 1.92, 95%CI 0.81 to 4.56). In conclusion, statin use during the 30 days prior to admission for COVID-19 was associated with a lower risk of developing severe COVID-19, and a faster time to recovery among patients without severe disease.

Background: Cirmtuzumab is a humanized monoclonal antibody that targets the receptor tyrosine kinase like orphan receptor 1 (ROR1), which is expressed on poor prognosis breast cancer, ovarian cancer, other solid tumors, CLL and mantle cell lymphoma. One clinical study showed increased expression of ROR1 in breast cancers after neoadjuvant chemotherapy and a preclinical PDX breast cancer model showed cirmtuzumab and paclitaxel to have at least additive efficacy1. A recently completed Phase 1 trial of cirmtuzumab in CLL showed the antibody to be both safe and effective in inhibiting tumor cell ROR1 signaling in patients with CLL2. Methods: The primary aim of this trial was to determine the safety of cirmtuzumab and weekly paclitaxel in patients with advanced Her2 negative breast cancer based upon dose limiting toxicities (DLTs) in the first cycle of treatment. Secondary endpoints were clinical activity, pharmacokinetics and correlative biomarkers on tumor specimens. Eligible patients were those with locally advanced, unresectable or metastatic Her2 negative breast cancer who had not received paclitaxel in the metastatic setting, had not developed metastatic disease within 6 months of (neo)adjuvant paclitaxel, had ECOG performance status of 0-2, and had adequate laboratory parameters. Any number of prior lines of therapy were allowed. Study treatment included fixed dose 600 mg cirmtuzumab given days 1 and 15 of cycle 1 and then day 1 of each subsequent 28-day cycle. Paclitaxel was given weekly at a dose of 80mg/m2. Patients were evaluated in dose cohorts of 5 for DLTs with a target of 15 evaluable patients. Results: To date, 6 patients evaluable for safety and 5 patients evaluable for DLTs were treated. Age range was 30 to 59 years. Three of 6 safety-evaluable patients had triple negative breast cancer at study enrollment. Prior lines of chemotherapy in the metastatic setting ranged from 0-3. No discontinuations for toxicity and no DLTs have been observed to date. Adverse events (AEs) have been consistent with the known safety profile of paclitaxel, with 3 episodes of grade 3 neutropenia in 2 patients and 1 episode of grade 3 hyperglycemia. All other AEs were grade 1 or 2. Partial responses have been observed in 2/5 patients with one patient response ongoing with cirmtuzumab alone for at least 17 weeks after stopping paclitaxel. Pharmacokinetic analysis of serial plasma samples for free unbound antibody from two patients provided results similar to those observed in CLL patients treated with cirmtuzumabwith a projected half-life of 30 days2. No decline in antibody concentration over time was observed consistent with the absence of neutralizing antibodies. Conclusions: Preliminary information indicates that the combination of fixed dose cirmtuzumab plus paclitaxel is well-tolerated and safe. Responses to therapy have been observed and preliminary pharmacokinetic results are consistent with sustained potentially therapeutic levels. Updated safety, clinical activity, pharmacokinetics and biomarker analyses will be presented. 1Zhang S et al. Proc Natl Acad Sci USA. 116(4): 1370-1377. PMID 30622177. 2Choi MY et al. Cell Stem Cell 22(6): 951-959. PMID 29859176. Funding sources: CIRM UC San Diego Alpha Stem Cell Clinic and Sanford Stem Cell Clinical Center; Oncternal Therapeutics, Inc.; UC San Diego Moores Cancer Center Padres Pedal the Cause Grant; Gonick Breast Cancer Research Fund Citation Format: Rebecca A Shatsky, Richard B Schwab, Teresa L Helsten, Emily I Pittman, Ruifeng Chen, James B Breitmeyer, Catriona HM Jamieson, Thomas J Kipps, Barbara A Parker. Phase 1b trial of cirmtuzumab and paclitaxel for locally advanced, unresectable and metastatic breast cancer [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P3-10-18.

BackgroundThe COVID-19 pandemic disrupted Alzheimer disease randomized clinical trials (RCTs)forcing investigators to make changes in the conduct of such trials while endeavoring to maintain their validity. Changing ongoing RCTs carries risks for biases and threats to validity. To understand the impact of exigent modifications due to COVID-19 we examined several scenarios in symptomatic and disease modification trials that could be made.MethodsWe identified both symptomatic and disease modification Alzheimer disease RCTs as exemplars of those that would be affected by the pandemic and considered the types of changes that sponsors could make to each. We modeled three scenarios for each of the types of trialsusing existing datasets, adjusting enrollment, follow-ups, and dropouts to examine the potential effects COVID-19-related changes.Simulations were performed that accounted for completion and dropout patterns using linear mixed effects models, modeling time as continuous and categorical. The statistical power of the scenarios was determined.ResultsTruncating both symptomatic and disease modification trials, led to underpowered trials.By contrast, adapting the trials byextending the treatment period, temporarily stopping treatment, delaying outcomes assessments, and performing remote assessment allowed for increased statistical power nearly to the level originally planned.DiscussionThese analyses support the idea that disrupted trials under common scenarios are better continued and extended even in the face of dropouts, treatment disruptions, missing outcomes, and other exigencies, and that adaptations can be made that maintain the trials validity. We suggest some adaptive methods to do this noting that some changes become under-powered to detect theoriginal effect sizes and expected outcomes. These analyses provide insight to better plan trials that are resilient to unexpected changes to the medical, social, and political milieu.

Background The US lags behind >120 countries in implementing graphic warning labels (GWLs) on cigarette packs. US courts prevented implementation of FDA's 2012 rule requiring GWLs citing the need for more evidence on effectiveness. After more research, in 2020, the FDA proposed a revised rule mandating GWLs. This trial will test how the introduction of GWLs influence cognitions and behavior in US smokers. Method To investigate the “real-world” impact of GWLs in US smokers, we are conducting a randomized trial involving a 3-month intervention and 8-month follow-up. The study recruited California smokers between September 2016 through December 2019 and randomly assigned them into 3 groups (1) Blank Pack devoid of any cigarette branding; (2) GWL Pack featuring 1 of 3 rotating images added to blank pack; or (3) their usual Standard US Pack. Throughout the 3-month intervention, participants purchased study-packaged cigarettes and reported daily cognitions and behavior through ecological momentary assessments. We will validate self-reported tobacco use with saliva cotinine concentrations following the 3-month intervention and 8-month follow-up. Results The trial enrolled 359 participants (average age 39 years; average cigarette consumption half a pack/day). The 3 study groups were balanced on age, gender, race-ethnicity, education and income (17% low income) as well as on smoking related variables. Conclusions This 3-month real-world randomized trial will test the effect of repackaging cigarettes from standard US packs to GWL plain packs on smokers' perceptions of the risks of smoking, their perception of the appeal of their cigarettes, and on their smoking behavior., Highlights • The efficacy of Graphic Warning Labels (GWLs) on Cigarette Packs has been disputed in US courts. • This trial randomly assigned US smokers to receive cigarettes in one of three study pack groups. • Study packs were:1-Blank Pack devoid of tobacco imagery; 2-GWL Pack; 3- Standard US pack. • We assessed smoking cognitions and behavior pre-randomization and during the intervention. • Smoking behavior is validated by saliva cotinine.

Background Immunotherapeutic regulation of the tumor microenvironment in prostate cancer patients is not understood. Most antibody immunotherapies have not succeeded in prostate cancer. We showed previously that high-risk PCa patients have a higher density of tumor infiltrating B-cells in prostatectomy specimens. In mouse models, anti-CD20 antibody ablation of B-cells delayed PCa regrowth post-treatment. We sought to determine whether neoadjuvant anti-CD20 immunotherapy with rituximab could reduce CD20+ B cell infiltration of prostate tumors in patients. Methods An open label, single arm clinical trial enrolled eight high-risk PCa patients to receive one cycle of neoadjuvant rituximab prior to prostatectomy. Eleven clinical specimens with similar characteristics were selected as controls. Treated and control samples were concurrently stained for CD20 and digitally scanned in a blinded fashion. A new method of digital image quantification of lymphocytes was applied to prostatectomy sections of treated and control cases. CD20 density was quantified by a deconvolution algorithm in pathologist-marked tumor and adjacent regions. Statistical significance was assessed by one sided Welch’s t-test, at 0.05 level using a gatekeeper strategy. Secondary outcomes included CD3+ T-cell and PD-L1 densities. Results Mean CD20 density in the tumor regions of the treated group was significantly lower than the control group (p = 0.02). Mean CD3 density in the tumors was significantly decreased in the treated group (p = 0.01). CD20, CD3 and PD-L1 staining primarily occurred in tertiary lymphoid structures (TLS). Neoadjuvant rituximab was well-tolerated and decreased B-cell and T-cell density within high-risk PCa tumors compared to controls. Conclusions This is the first study to treat patients prior to surgical prostate removal with an immunotherapy that targets B-cells. Rituximab treatment reduced tumor infiltrating B and T-cell density especially in TLSs, thus, demonstrating inter-dependence between B- and T-cells in prostate cancer and that Rituximab can modify the immune environment in prostate tumors. Future studies will determine who may benefit from using rituximab to improve their immune response against prostate cancer. Trial registration NCT01804712, March 5th, 2013 https://clinicaltrials.gov/ct2/show/NCT01804712?cond=NCT01804712&draw=2&rank=1

Purpose Cancer ascertainment using large-scale electronic health records is a challenge. Our aim was to propose and apply a structured approach for evaluating multiple candidate approaches for cancer ascertainment using colorectal cancer (CRC) ascertainment within the US Department of Veterans Affairs (VA) as a use case. Methods The proposed approach for evaluating cancer ascertainment strategies includes assessment of individual strategy performance, comparison of agreement across strategies, and review of discordant diagnoses. We applied this approach to compare three strategies for CRC ascertainment within the VA: administrative claims data consisting of International Classification of Diseases, Ninth Revision (ICD9) diagnosis codes; the VA Central Cancer Registry (VACCR); and the newly accessible Oncology Domain, consisting of cases abstracted by local cancer registrars. The study sample consisted of 1,839,043 veterans with index colonoscopy performed from 1999 to 2014. Strategy-specific performance was estimated based on manual record review of 100 candidate CRC cases and 100 colonoscopy controls. Strategies were further compared using Cohen’s κ and focused review of discordant CRC diagnoses. Results A total of 92,197 individuals met at least one CRC definition. All three strategies had high sensitivity and specificity for incident CRC. However, the ICD9-based strategy demonstrated poor positive predictive value (58%). VACCR and Oncology Domain had almost perfect agreement with each other (κ, 0.87) but only moderate agreement with ICD9-based diagnoses (κ, 0.51 and 0.57, respectively). Among discordant cases reviewed, 15% of ICD9-positive but VACCR- or Oncology Domain–negative cases had incident CRC. Conclusion Evaluating novel strategies for identifying cancer requires a structured approach, including validation against manual record review, agreement among candidate strategies, and focused review of discordant findings. Without careful assessment of ascertainment methods, analyses may be subject to bias and limited in clinical impact.

Background Statins have anti-inflammatory and immunomodulatory effects that may reduce the severity of coronavirus disease 2019 (COVID-19), in which organ dysfunction is mediated by severe inflammation. Large studies with diverse populations evaluating statin use and outcomes in COVID-19 are lacking. Methods and results We used data from 10,541 patients hospitalized with COVID-19 through September 2020 at 104 US hospitals enrolled in the American Heart Association’s COVID-19 Cardiovascular Disease (CVD) Registry to evaluate the associations between statin use and outcomes. Prior to admission, 42% of subjects (n = 4,449) used statins (7% on statins alone, 35% on statins plus anti-hypertensives). Death (or discharge to hospice) occurred in 2,212 subjects (21%). Outpatient use of statins, either alone or with anti-hypertensives, was associated with a reduced risk of death (adjusted odds ratio [aOR] 0.59, 95% CI 0.50–0.69), adjusting for demographic characteristics, insurance status, hospital site, and concurrent medications by logistic regression. In propensity-matched analyses, use of statins and/or anti-hypertensives was associated with a reduced risk of death among those with a history of CVD and/or hypertension (aOR 0.68, 95% CI 0.58–0.81). An observed 16% reduction in odds of death among those without CVD and/or hypertension was not statistically significant. Conclusions Patients taking statins prior to hospitalization for COVID-19 had substantially lower odds of death, primarily among individuals with a history of CVD and/or hypertension. These observations support the continuation and aggressive initiation of statin and anti-hypertensive therapies among patients at risk for COVID-19, if these treatments are indicated based upon underlying medical conditions.

// Johnny C. Akers 1,* , Wei Hua 2,* , Hongying Li 3,* , Valya Ramakrishnan 1 , Zixiao Yang 2 , Kai Quan 2 , Wei Zhu 2 , Jie Li 1 , Javier Figueroa 1 , Brian R. Hirshman 1 , Brittney Miller 1 , David Piccioni 4 , Florian Ringel 5 , Ricardo Komotar 6 , Karen Messer 3 , Douglas R. Galasko 7 , Fred Hochberg 1 , Ying Mao 7,8,** , Bob S. Carter 1,** and Clark C. Chen 1,** 1 Center for Theoretical and Applied Neuro-Oncology, University of California, San Diego, CA, USA 2 Department of Neurosurgery, Huashan Hospital, Fudan University, Shanghai, China 3 Biostatistics Department, Moores Cancer Center, UC San Diego Health System, La Jolla, CA, USA 4 Department of Neurosurgery, Moores Cancer Center, UC San Diego Health System, La Jolla, CA, USA 5 Department of Neurosurgery, Klinikum rechts der Isar, Technische Universitat Munchen, Munich, Germany 6 Department of Neurological Surgery, Miller School of Medicine, University of Miami, Miami, FL, USA 7 Department of Neurosciences, University of California, San Diego, CA, USA 8 State Key Laboratory of Medical Neurobiology, Institutes of Brain Science, The Collaborative Innovation Center for Brain Science, Fudan University, Shanghai, China * These authors shared responsibility as first authors ** These authors shared responsibility as senior authors Correspondence to: Clark C. Chen, email: // Keywords : extracellular vesicle, CSF, liquid biopsy Received : April 12, 2017 Accepted : May 19, 2017 Published : June 01, 2017 Abstract Purpose: To develop a cerebrospinal fluid (CSF) miRNA diagnostic biomarker for glioblastoma. Experimental Design: Glioblastoma tissue and matched CSF from the same patient (obtained prior to tumor manipulation) were profiled by TaqMan OpenArray ® Human MicroRNA Panel. CSF miRNA profiles from glioblastoma patients and controls were created from three discovery cohorts and confirmed in two validation cohorts. Results: miRNA profiles from clinical CSF correlated with those found in glioblastoma tissues. Comparison of CSF miRNA profiles between glioblastoma patients and non-brain tumor patients yielded a tumor “signature” consisting of nine miRNAs. The “signature” correlated with glioblastoma tumor volume ( p =0.008). When prospectively applied to cisternal CSF, the sensitivity and specificity of the ‘signature’ for glioblastoma detection were 67% and 80%, respectively. For lumbar CSF, the sensitivity and specificity of the signature were 28% and 95%, respectively. Comparable results were obtained from analyses of CSF extracellular vesicles (EVs) and crude CSF. Conclusion: We report a CSF miRNA signature as a “liquid biopsy” diagnostic platform for glioblastoma.

Background: There is substantial variation in breast cancer survival rates, even among patients with similar clinical and genomic profiles. New biomarkers are needed to improve risk stratification and inform treatment options. Our aim was to identify novel miRNAs associated with breast cancer survival and quantify their prognostic value after adjusting for established clinical factors and genomic markers. Methods: Using the Women's Healthy Eating and Living (WHEL) breast cancer cohort with >15 years of follow-up and archived tumor specimens, we assayed PAM50 mRNAs and 25 miRNAs using the Nanostring nCounter platform. Results: We obtained high-quality reads on 1,253 samples (75% of available specimens) and used an existing research-use algorithm to ascertain PAM50 subtypes and risk scores (ROR-PT). We identified miRNAs significantly associated with breast cancer outcomes and then tested these in independent TCGA samples. miRNAs that were also prognostic in TCGA samples were further evaluated in multiple regression Cox models. We also used penalized regression for unbiased discovery. Conclusions: Two miRNAs, 210 and 29c, were associated with breast cancer outcomes in the WHEL and TCGA studies and further improved risk stratification within PAM50 risk groups: 10-year survival was 62% in the node-negative high miR-210-high ROR-PT group versus 75% in the low miR-210- high ROR-PT group. Similar results were obtained for miR-29c. We identified three additional miRNAs, 187-3p, 143-3p, and 205-5p, via penalized regression. Impact: Our findings suggest that miRNAs might be prognostic for long-term breast cancer survival and might improve risk stratification. Further research to incorporate miRNAs into existing clinicogenomic signatures is needed.

Author(s): Pierce, John P; Messer, Karen; Leas, Eric C; Kealey, Sheila; White, Martha M; Benmarhnia, Tarik

BackgroundElectronic cigarettes (e-cigarettes) are heavily marketed and widely perceived as helpful for quitting or reducing smoking intensity. We test whether ever-use of e-cigarettes among early adopters was associated with: 1) increased cigarette smoking cessation; and 2) reduced cigarette consumption.MethodsA representative cohort of U.S. smokers (N = 2454) from the 2010 Tobacco Use Supplement to the Current Population Survey (TUS-CPS) was re-interviewed 1year later. Outcomes were smoking cessation for 30+ days and change in cigarette consumption at follow-up. E-cigarettes use was categorized as for cessation purposes or for another reason. Multivariate regression was used to adjust for demographics and baseline cigarette dependence level.ResultsIn 2011, an estimated 12% of adult U.S. smokers had ever used e-cigarettes, and 41% of these reported use to help quit smoking. Smokers who had used e-cigarettes for cessation were less likely to be quit for 30+ days at follow-up, compared to never-users who tried to quit (11.1% vs 21.6%; ORadj = 0.44, 95 % CI = 0.2-0.8). Among heavier smokers at baseline (15+ cigarettes per day (CPD)), ever-use of e-cigarettes was not associated with change in smoking consumption. Lighter smokers (

Background: Venetoclax (Ven)-based regimens are highly effective in treating patients with chronic lymphocytic leukemia (CLL), effecting clearance of detectable minimal residual disease (MRD) in many patients after just 1 year of therapy. Approximately, 30% of patients fail to clear detectable MRD within this time period and risk developing, progressive disease (PD) despite continued Ven therapy. Moreover, these patients have a relatively short progression free survival (PFS) after stopping fixed-duration therapy. Therefore, development of consolidation strategies to eradicate detectable MRD and/or to mitigate the risk of PD in patients who fail to clear MRD after 1 year of Ven-based therapy is of vital clinical importance. In particular, patients who fail to clear MRD after 1 year of Ven-based therapy harbor CLL cells with high-level expression of ROR1, an oncoembryonic protein expressed by a broad array of incurable malignancies. Patients who are refractory to MRD-clearance on Ven-based therapies have gene-expression signatures reflective of high-level ROR1-signaling, which can be inhibited by the anti-ROR1 mAb, Cirmtuzumab (Choi et al., Cell Stem Cell. 2018; 22: 951-959). Prior studies demonstrated that Cirmtuzumab and Ven have at least additive activity in promoting cytotoxicity of CLL cells in vitro (Rassenti et al. PNAS. 2017;114(40):10731-10736). As such, cirmtuzumab may be an effective consolidation strategy for patients who fail to clear MRD following completing 1 year of Ven-based therapy. Study Design and Methods: Study Design: We initiated a single center, phase 2 Simon's two-stage-designed study to determine the efficacy of Cirmtuzumab plus Ven combination therapy in patients who fail to clear detectable MRD (defined as > 0.01% of the blood mononuclear cells, as assessed by flow cytometry) after ≥1 year of Ven-based therapy (NCT04501939). Enrolled patients will receive cirmtuzumab at 600 mg IV, q14 days for 2 doses and then monthly thereafter. Patients will continue oral Ven at 400mg daily and be monitored for safety and PD. Following 6 months of Cirmtuzumab + Ven, patients will be assessed for MRD in the blood. At the discretion of the treating physician, patients may continue combination treatment for up to one year (Figure 1). Major Eligibility Criteria: Patients must have a diagnosis of CLL with detectable MRD after having received ≥ 12 months of Ven-based treatment . Patients will be excluded from the study if they have an uncontrolled medical co-morbidity, which compromises their capacity to complete the study, or if they are receiving treatment for CLL with agents other than Ven. End Points: The primary end-point of the proposed study is clearance of detectable MRD in the blood after 6 months of cirmtuzumab + Ven therapy. Secondary end-points include safety and time to next CLL treatment. Exploratory end-points include changes in gene expression in leukemia cells, including analysis of archival pre-Ven treatment samples, when available. Statistical Methods: We used a Simon's two-stage minimax design at 5% significance level to test the scientific hypothesis that 6 cycles of cirmtuzumab + Ven will achieve undetectable MRD (a 'response') in more than 5% of patients, against the null hypothesis of less than a 5% response rate. In the first stage, we plan to accrue 12 patients. If none of these patients respond at 6 months, the study will close. Otherwise, we will accrue an additional 4 patients for a total of 16 patients. If three or more patients respond, the primary endpoint of the trial will have been met, demonstrating an MRD clearance rate greater than 5%. The trial is designed to have 80% power to provide such evidence at the 5% significance level if the true rate of clearance of MRD is 25% or greater. Disclosures Heyman: Oncternal Therapeutics, INC: Research Funding. Choi:Pharmacyclics/Abbvie: Research Funding; Genentech: Consultancy. Jamieson:Forty Seven Inc: Patents & Royalties; Bristol-Myers Squibb: Other. Kipps:Genentech/Roche: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; VelosBio: Research Funding; Oncternal Therapeutics, Inc.: Other: Cirmtuzumab was developed by Thomas J. Kipps in the Thomas J. Kipps laboratory and licensed by the University of California to Oncternal Therapeutics, Inc., which provided stock options and research funding to the Thomas J. Kipps laboratory, Research Funding; Celgene: Honoraria, Research Funding; Ascerta/AstraZeneca, Celgene, Genentech/F. Hoffmann-La Roche, Gilead, Janssen, Loxo Oncology, Octernal Therapeutics, Pharmacyclics/AbbVie, TG Therapeutics, VelosBio, and Verastem: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pharmacyclics/ AbbVie, Breast Cancer Research Foundation, MD Anderson Cancer Center, Oncternal Therapeutics, Inc., Specialized Center of Research (SCOR) - The Leukemia and Lymphoma Society (LLS), California Institute for Regenerative Medicine (CIRM): Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau.

Three cigarette smoking behaviors influence lung cancer rates: how many people start, the amount they smoke, and the age they quit. California has reduced smoking faster than the rest of the United States and trends in these three smoking behaviors should inform lung cancer trends. We examined trends in smoking behavior (initiation, intensity, and quitting) in California and the rest of United States by regression models using the 1974–2014 National Health Interview Surveys (n = 962,174). Lung cancer mortality data for 1970–2013 was obtained from the National Surveillance, Epidemiology, and End Results (SEER) Program. Among those aged 18 to 35 years, California had much larger declines than the rest of the United States in smoking initiation and intensity, and increased quitting. In 2012–2014, among this age group, only 18.6% [95% confidence interval (CI), 16.8%–20.3%] had ever smoked; smokers consumed only 6.3 cigarettes/day (95% CI, 5.6–7.0); and 45.7% (95% CI, 41.1%–50.4%) of ever-smokers had quit by age 35. Each of these metrics was at least 24% better than in the rest of the United States. There was no marked California effect on quitting or intensity among seniors. From 1986 to 2013, annual lung cancer mortality decreased more rapidly in California and by 2013 was 28% lower (62.6 vs. 87.5/100,000) than in the rest of the United States. California's tobacco control efforts were associated with a major reduction in cigarette smoking among those under age 35 years. These changes will further widen the lung cancer gap that already exists between California and the rest of the United States.

Purpose: A Phase 3 randomized study (COG ANBL0032) demonstrated significantly improved outcome by adding immunotherapy with ch14.18 antibody to isotretinoin as post-consolidation therapy for high-risk neuroblastoma (NB). This study, ANBL0931, was designed to collect FDA-required safety/toxicity data to support FDA registration of ch14.18. Experimental Design: Newly diagnosed high-risk NB patients who achieved at least a partial response to induction therapy and received myeloablative consolidation with stem cell rescue were enrolled to receive 6 courses of isotretinoin with five concomitant cycles of ch14.18 combined with GM-CSF or IL2. Ch14.18 infusion time was 10-20 hours per dose. Blood was collected for cytokine analysis and its association with toxicities and outcome. Results: Of 105 patients enrolled, five patients developed protocol-defined unacceptable toxicities. The most common Grade ≥3 non-hematologic toxicities of immunotherapy for cycles 1-5, respectively, were neuropathic pain (41%, 28%, 22%, 31%, 24%), hypotension (10%, 17%, 4%, 14%, 8%), allergic reactions (3%, 10%, 5%, 7%, 2%), capillary leak syndrome (1%, 4%, 0%, 2%, 0%), and fever (21%, 59%, 6%, 32%, 5%). The 3-year event-free survival and overall survival were 67.6±4.8% and 79.1±4.2%, respectively. Allergic reaction during course 1 was associated with elevated serum levels of IL-1Ra and IFN, while severe hypotension during this course was associated with low IL5 and nitrate. Higher pretreatment CXCL9 level was associated with poorer EFS. Conclusions: This study has confirmed the significant, but manageable treatment-related toxicities of this immunotherapy and identified possible cytokine biomarkers associated with select toxicities and outcome. EFS and OS appear similar to that previously reported on ANBL0032.

A positive surgical margin (PSM) following cancer resection oftentimes necessitates adjuvant treatments and carries significant financial and prognostic implications. We sought to compare PSM rates for the ten most common solid cancers in the United States, and to assess trends over time. Over 10 million patients were identified in the National Cancer Data Base from 1998–2012, and 6.5 million had surgical margin data. PSM rates were compared between two time periods, 1998–2002 and 2008–2012. PSM was positively correlated with tumor category and grade. Ovarian and prostate cancers had the highest PSM prevalence in women and men, respectively. The highest PSM rates for cancers affecting both genders were seen for oral cavity tumors. PSM rates for breast cancer and lung and bronchus cancer in both men and women declined over the study period. PSM increases were seen for bladder, colon and rectum, and kidney and renal pelvis cancers. This large-scale analysis appraises the magnitude of PSM in the United States in order to focus future efforts on improving oncologic surgical care with the goal of optimizing value and improving patient outcomes.

Objective: To describe a framework for leveraging big data for research and quality improvement purposes and demonstrate implementation of the framework for design of the Department of Veterans Affairs (VA) Colonoscopy Collaborative.Methods: We propose that research utilizing large-scale electronic health records (EHRs) can be approached in a 4 step framework: 1) Identify data sources required to answer research question; 2) Determine whether variables are available as structured or free-text data; 3) Utilize a rigorous approach to refine variables and assess data quality; 4) Create the analytic dataset and perform analyses. We describe implementation of the framework as part of the VA Colonoscopy Collaborative, which aims to leverage big data to 1) prospectively measure and report colonoscopy quality and 2) develop and validate a risk prediction model for colorectal cancer (CRC) and high-risk polyps.Results: Examples of implementation of the 4 step framework are provided. To date, we have identified 2,337,171 Veterans who have undergone colonoscopy between 1999 and 2014. Median age was 62 years, and 4.6 percent (n = 106,860) were female. We estimated that 2.6 percent (n = 60,517) had CRC diagnosed at baseline. An additional 1 percent (n = 24,483) had a new ICD-9 code-based diagnosis of CRC on follow up.Conclusion: We hope our framework may contribute to the dialogue on best practices to ensure high quality epidemiologic and quality improvement work. As a result of implementation of the framework, the VA Colonoscopy Collaborative holds great promise for 1) quantifying and providing novel understandings of colonoscopy outcomes, and 2) building a robust approach for nationwide VA colonoscopy quality reporting.

Introduction Treatment with hypomethylating agent therapy might enhance anti-CD33 monoclonal antibody-mediated cytotoxicity against acute myeloid leukemia (AML) blasts through epigenetic effects on Syk and SHP-1 expression. Patients and Methods In the present phase I/II study, we treated patients with relapsed or refractory AML with azacitidine, followed by 2 doses of gemtuzumab ozogamicin (GO) at 6 mg/m2, the Food and Drug Administration-approved dose and schedule at study initiation. We sought to determine the maximum tolerated dose and clinical activity of this combination therapy. Secondarily, we aimed to determine whether baseline Syk and SHP-1 expression can be used as predictive biomarkers of treatment response. Results The established maximum tolerated dose was azacitidine 75 mg/m2 daily for 6 consecutive days, followed by GO 6 mg/m2 on days 7 and 21. Of the 50 evaluable patients, 12 (24%) obtained complete remission (CR) or CR with incomplete peripheral blood recovery (CRp). No dose-limiting toxicities were observed in phase I, and no patient developed hepatic sinusoidal obstructive syndrome. Although no significant correlation was found between Syk and SHP-1 expression and the clinical response to combination therapy, in vitro studies repeatedly demonstrated that azacitidine-treated AML cells had an increased response to GO treatment. Conclusion Our study found that the combination of GO with azacitidine is relatively well tolerated, with response rates similar to those with GO monotherapy at higher doses. Differences in the GO drug schedule, dose level, and frequency might explain the discrepant response rates between our study and others, suggesting that the optimal GO dose remains unclear, especially when combined with hypomethylating agent therapy.

Author(s): Hussain, Timon; Savariar, Elamprakash N; Diaz-Perez, Julio A; Messer, Karen; Pu, Minya; Tsien, Roger Y; Nguyen, Quyen T | Abstract: BackgroundWe evaluated the use of intraoperative fluorescence guidance by enzymatically cleavable ratiometric activatable cell-penetrating peptide (RACPPPLGC(Me)AG) containing Cy5 as a fluorescent donor and Cy7 as a fluorescent acceptor for salivary gland cancer surgery in a mouse model.MethodsSurgical resection of small parotid gland cancers in mice was performed with fluorescence guidance or white light (WL) imaging alone. Tumor identification accuracy, operating time, and tumor-free survival were compared.ResultsRACPP guidance aided tumor detection (positive histology in 90% [27/30] vs 48% [15/31] for WL; p l .001). An approximate 25% ratiometric signal increase as the threshold to distinguish between tumor and adjacent tissue, yielded g90% detection sensitivity and specificity. Operating time was reduced by 54% (p l .001), and tumor-free survival was increased with RACPP guidance (p = .025).ConclusionRACPP provides real-time intraoperative guidance leading to improved survival. Ratiometric signal thresholds can be set according to desired detection accuracy levels for future RACPP applications.

We examined the extracellular vesicle (EV) and RNA composition of pooled normal cerebrospinal fluid (CSF) samples and CSF from five major neurological disorders: Alzheimer’s disease (AD), Parkinson’s disease (PD), low-grade glioma (LGG), glioblastoma multiforme (GBM), and subarachnoid haemorrhage (SAH), representing neurodegenerative disease, cancer, and severe acute brain injury. We evaluated: (I) size and quantity of EVs by nanoparticle tracking analysis (NTA) and vesicle flow cytometry (VFC), (II) RNA yield and purity using four RNA isolation kits, (III) replication of RNA yields within and between laboratories, and (IV) composition of total and EV RNAs by reverse transcription–quantitative polymerase chain reaction (RT-qPCR) and RNA sequencing (RNASeq). The CSF contained ~106 EVs/μL by NTA and VFC. Brain tumour and SAH CSF contained more EVs and RNA relative to normal, AD, and PD. RT-qPCR and RNASeq identified disease-related populations of microRNAs and messenger RNAs (mRNAs) relative to normal CSF, in both total and EV fractions. This work presents relevant measures selected to inform the design of subsequent replicative CSF studies. The range of neurological diseases highlights variations in total and EV RNA content due to disease or collection site, revealing critical considerations guiding the selection of appropriate approaches and controls for CSF studies.

Background The efficacy of sentinel lymph node (SLN) surgery requires targeted removal of first-draining nodes; however, frequently more nodes are removed than necessary. [99mTc]tilmanocept (TcTM) is a molecular-targeted radiopharmaceutical specifically designed for SLN mapping. We evaluated technical outcomes of SLN biopsy in breast cancer patients mapped with TcTM + vital blue dye (VBD) versus filtered [99mTc]sulfur colloid (fTcSC) + VBD. Methods There were 84 versus 115 patients in the TcTM versus fTcSC cohorts, respectively. Main measures were the number of SLNs removed per patient and factors influencing number of nodes removed. We also evaluated whether the radiotracer injected affected the proportion of positive nodes removed in node-positive patients. Results Fewer nodes were removed among patients mapped with TcTM compared to fTcSC (mean TcTM: 1.85 vs. fTcSC: 3.24, p

NLR inflammasomes, caspase 1 activation platforms critical for processing key pro-inflammatory cytokines, have been implicated in the development of nonalcoholic fatty liver disease (NAFLD). As the direct role of the NLRP3 inflammasome remains unclear, we tested effects of persistent NLRP3 activation as a contributor to NAFLD development and, in particular, as a modulator of progression from benign hepatic steatosis to steatohepatitis during diet-induced NAFLD. Gain of function tamoxifen-inducible Nlrp3 knock-in mice allowing for in vivo temporal control of NLRP3 activation and loss of function Nlrp3 knockout mice were placed on short-term choline-deficient amino acid-defined (CDAA) diet, to induce isolated hepatic steatosis or long-term CDAA exposure, to induce severe steatohepatitis and fibrosis, respectively. Expression of NLRP3 associated proteins was assessed in liver biopsies of a well-characterized group of patients with the full spectrum of NAFLD. Nlrp3−/− mice were protected from long-term feeding CDAA-induced hepatomegaly, liver injury, and infiltration of activated macrophages. More importantly, Nlrp3−/− mice showed marked protection from CDAA-induced liver fibrosis. After 4 weeks on CDAA diet, wild-type (WT) animals showed isolated hepatic steatosis while Nlrp3 knock-in mice showed severe liver inflammation, with increased infiltration of activated macrophages and early signs of liver fibrosis. In the liver samples of patients with NAFLD, inflammasome components were significantly increased in those patients with nonalcoholic steatohepatitis (NASH) when compared to those with non-NASH NAFLD with mRNA levels of pro-IL1 beta correlated to levels of COL1A1. Our study uncovers a crucial role for the NLRP3 inflammasome in the development of NAFLD. These findings may lead to novel therapeutic strategies aimed at halting the progression of hepatic steatosis to the more severe forms of this disease. Fil: Wree, Alexander. University of California at San Diego; Estados Unidos. University Hospital Essen; Alemania Fil: McGeough, Matthew D.. University of California at San Diego; Estados Unidos Fil: Peña, Carla A.. University of California at San Diego; Estados Unidos Fil: Schlattjan, Martin. University Hospital Essen; Alemania Fil: Li, Hongying. University of California at San Diego; Estados Unidos Fil: Inzaugarat, Maria Eugenia. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Inmunología, Genética y Metabolismo. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Inmunología, Genética y Metabolismo; Argentina Fil: Messer, Karen. University of California at San Diego; Estados Unidos Fil: Canbay, Ali. University Hospital Essen; Alemania Fil: Hoffman, Hal M.. University of California at San Diego; Estados Unidos. Ludwig Institute of Cancer Research; Estados Unidos Fil: Feldstein, Ariel E.. University of California at San Diego; Estados Unidos

Background Medical management is the cornerstone of malignant bowel obstruction (MBO) therapy and may include antisecretory agents such as octreotide. Currently, no data exist regarding octreotide prescribing patterns inUS academic hospitals in the palliation of inoperable MBO. The aim of this study is to collect octreotide prescribing data to shape future prospective studies. Methods This retrospective chart review evaluated inpatient inoperable MBO admissions at a single academic US hospital between 2008 and 2011. The prescribing primary service (medical vs. surgical), inpatient day initiated, average octreotide daily dose, cumulative octreotide dose, days receiving octreotide, length of stay (LOS), subject age, cancer stage, lines of chemotherapy, cancer type, and overall survival were analyzed utilizing a Wilcoxon rank sum test, Spearman rank correlation test, Kaplan–Meier curves, log rank test, and multiple linear regression analysis when appropriate. Results A total of 767 patients received octreotide. A cancer diagnosis was documented in 134 patients and 37 of these (24 females and 13 males; mean age, 56.7 years) had a confirmed inoperable MBO. Statistical significance was not achieved for variables analyzed. However, octreotide prescribing trends were observed for several variables: the mean LOS was equivalent onboth services (16.8 vs. 17days), mean octreotide dose was higher on the medical service (201.2 μg vs.119 μgsurgical),cumulativeoctreotidedosewashigheron the medical service (3,558 vs. 1,884 mcg), mean day of octreotide initiation was roughly equivalent (7.9 days medical vs. 8.8 days surgical), subjects on the medical service had a decreased overall survival, and earlier octreotide initiation (defined as

BackgroundCytoreductive surgery with hyperthermic intraperitoneal chemotherapy (CRS-HIPEC) has an emerging role in the treatment of peritoneal malignancies. The CRS-HIPEC approach has known treatment-related toxicities. This study sought to determine the predictors of major postoperative complications after CRS-HIPEC in a high-volume center.MethodsFrom a single-institution database, this study investigated complications experienced by patients undergoing CRS-HIPEC. Multiple preoperative and operative factors were analyzed for their ability to predict 60-day Clavien grade 3 and greater (major) complications by logistic regression. A predictive model was created from preoperative factors using multivariate logistic regression. The model was tested by Akaike's information criterion, the Hosmer and Lemeshow Goodness-of-Fit Test, the receiver operating characteristic, and the Youden Index.ResultsThe study evaluated 247 patients undergoing CRS-HIPEC. The primary tumor site was the appendix in 166 cases (67.2%), the colorectal area in 51 cases (20.6 %), the peritoneum (mesothelioma) in 22 cases (8.9%), the ovary in 5 cases (2%), and the small bowel in 3 cases (1.2%). The median peritoneal cancer index was 14 (range 0-29), and 235 patients (95.1%) had a complete (CC-0/1) cytoreduction. Major complications occurred for 41 patients (16.6%), classified as grade 3 in 33 cases (13.4%), grade 4 in 5 cases (2%), and grade 5 (deaths) in 3 cases (1.2%). The factors predictive of major complications in the multivariate analysis were a Charlson Comorbidity Index (CCI) score higher than 0 [odds ratio (OR), 2.505; p = 0.035], presence of preoperative symptoms (OR 1.951; p = 0.064), and prior resection status [no resection or prior CRS-HIPEC (OR 2.087) vs. prior resection without CRS-HIPEC (OR 3.209); p = 0.046]. These variables were used to create a tool predictive of postoperative complications.ConclusionPresence of symptoms, CCI, and prior resection status predict major complications and define a low-risk population after CRS-HIPEC.

Background: Prior work suggests that synchronous bilateral breast cancers may be clonal, with one tumor a metastasis, although prior techniques lacked resolution to prove this relationship. We used deep whole exome and shallow whole genome sequencing to compare bilateral tumors in two cases. In both cases, tumors were invasive and node negative with one tumor ER+/PR+/HER2− (HR+) lobular and the other triple negative (TN) ductal. Case 1 is a 75-year-old African American woman and Case 2 a 70-year-old white woman. With 44 and 12 months of follow up, respectively, neither patient has recurred. Methods: Agilent SureSelect All Exon 50Mb Target Enrichment Kits were used for exome capture. Paired-end sequencing was performed with 200 base pair reads on the Illumina HiSeq 2000. Sequencing depth was targeted to cover 80% of the genome at 100x for three tumors with 70% cellularity, 200x for one tumor with 40% cellularity and 30x for germline. Tumor and germline exome results were compared to identify high confidence somatic single nucleotide variants (HC SNV). HC SNV's were called using GATK and stringent custom filtering to avoid false positives resulting from unrecognized germline single nucleotide polymorphisms. For each tumor pair, we define a clonality likelihood score (CLS) as the ratio of the number of HC SNV called at the same site and with the same alternate base in both tumors, to the total number of sites with an HC SNV called in either tumor. For comparison we analyzed the called SNV data from The Cancer Genome Atlas (TCGA) for exome sequenced HR+ or TN breast cancers. Results: In Case 1, of 102 HC SNVs called in either tumor, 82 were shared, for a CLS of 80.3%. Additionally, 11 shared SNVs were synonymous, consistent with clonality. Lastly the non-shared HC SNVs were asymmetrically found in the TN tumor, consistent with clonal evolution during metastasis. Copy number analysis (CNA) showed Case 1 to have a deletion in 6q, including the ESR1 gene, unique to the TN tumor. To assess significance of the CLS, we found three primary/metastatic clonal pairs in the TCGA to serve as positive controls. To serve as negative controls, from 357 ER+ and 46 TN primary TCGA tumors, we formed a total of 16,422 independent ER+/TN pairs. For the 3 clonal TCGA pairs, the CLS values were 39.3%, 58.5% and 60.0%. Most of the independent TCGA pairs had a CLS of zero (98.5%), with a maximum CLS of 2.8%. As the CLS for Case 1 lies above maximum observed CLS among 16,422 independent tumor pairs, we reject the hypothesis that this tumor pair is independent, at p < 0.0001. For Case 2, of 222 HC SNV sites, 5 were shared for a CLS of 2.3%, consistent with independence. Conclusion: Somatic single nucleotide mutations identified by exome sequencing found that the two tumors in Case 1 share >80% of SNVs, consistent with clonal evolution of metastasis. The two tumors from Case 2 have few shared SNVs, consistent with independent origin. CNA results were consistent. This is the first clonality analysis reported from deep sequencing of phenotypically discordant synchronous bilateral breast cancers, and demonstrates that next-generation sequencing can distinguish clonal from independent tumor pairs with high confidence. Funding: The Breast Cancer Research Foundation Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P2-06-01.

Background Public health campaigns have reduced the exposure of U.S. children to secondhand smoke at home; however, these may not have been equally effective across subgroups. Purpose To examine prevalence of home smoking bans among U.S. households with both children and smokers, over time and by demographic subgroups. Methods The Tobacco Use Supplement to the Current Population Survey (TUS-CPS) is a nationally representative household survey of tobacco use. The 1992/1993 and 2006/2007 TUS-CPS interviewed 22,746 households from a major racial/ethnic group with both children and adult smokers. Predictors of complete home smoking bans among demographic subgroups were identified using multivariate logistic regression. Analyses were conducted in 2010–2011. Results Complete home smoking bans among U.S. households with children and smokers (smoking families) more than tripled, from 14.1% in 1992/1993 to 50.0% in 2006/2007. However, non-Hispanic white and African-American smoking families lagged behind Asian/Pacific Islanders and Hispanics. In 2006/2007, 67.2% of African-American smoking families allowed smoking in the home, as did 59.2% of smoking families with all children aged ≥14 years. Bans were more likely among more-educated households and in states with lower adult smoking prevalence; however, these differences were attenuated in some racial/ethnic groups. Conclusions As of 2006/2007, only half of U.S. households with both children and smokers had complete home smoking bans. Home bans were less common among smoking families with older children, in African-American households, and in Hispanic or non-Hispanic white households in states with high smoking prevalence. Interventions are needed to promote smokefree homes among these groups.

Purpose: We report our single-institution experience using hypofractionated radiotherapy in a patient population 75 years and older diagnosed with stage IA or IB (T1/T2 N0) Non-Small Cell Lung Carcinoma. Materials and methods: This is a single-institution, retrospective analysis examining disease free and overall survival and toxicity after hypofractionated radiation therapy in a patient population 75 years and older diagnosed with stage IA or IB (T1/T2 N0) NSCLC. Between 1991 and 2005, a total of 33 such patients were identified with a median age of 79 years. Patients were treated with a median total dose of 7000 cGy using median daily dose fractions of 250 cGy. Analysis of competing risks (local failure, distal failure or death as the first event) was performed and cumulative incidence functions (CIF) were estimated. Results: The median length of follow-up was 19.8 months (range: 4.3 - 103.8 months). Of the 33 patients treated, 21 (63.6% of total) had no evidence of disease recurrence on follow-up imaging over the course of the study. Of the 12 patients with disease recurrence, 6 (18.2% of total) had local failure as the first event and 6 (18.2% of total) had distant metastasis as the first event. Analysis of competing risks showed that at 5 years, the probability of local failure as the first detected event was 19.5% (95%CI: 7.6%, 35.6%); the probability of distal failure as the first detected event was 21.5% (95%CI: 7.9%,39.4%); and the probability of death without recording a failure was 44.1% (95%CI: 26.1%, 60.7%). There were no treatment related deaths reported. Conclusions: Elderly patients diagnosed with stage I non-small cell lung cancer may safely be offered hypofractionated radiotherapy as an effective option with curative intent.

BACKGROUND: Polyinosinic-Polycytidylic acid stabilized with polylysine and carboxymethylcellulose (poly-ICLC) is a double stranded RNA that acts as a ligand for the Toll Receptor 3 (TLR3) and results in a broad host defense stimulation, including T-cell and natural killer cell activation and cytokine release (interferons alpha, beta, and gamma, interleukins, corticosteroids, and TNF). The goal of this trial is to determine the efficacy of this novel immunotherapy against refractory pediatric low-grade glioma (LGG). Here we present the results for the neurofibromatosis group. METHODS: Poly-ICLC 20mcg/kg/dose IM was self-administered twice a week at home for up to 24 cycles. Each cycle is 28 days. Endpoints include objective tumor response rate, progression-free survival (PFS), and rate of stabilization/improvement in visual examination in those with optic pathway glioma. RESULTS: Twenty three patients were enrolled, six with NF-1. Of NF1 patients (3 males, 3 females), five were evaluable, ages 1–16 years. Tumor location: 4 optic pathway, one thalamic, one cervico-medullary junction. 5/6 had received more than 2 prior regimens (range 1–7). Responses (PR+SD) were observed in 4/5 (80%), with 2 SD having a decrease in tumor size by 35% and 10%, one of whom had significant improvement on visual field testing, and 2 PR having decrease in tumor size by 50% and 55%. Only low grade toxicities were observed with poly-ICLC, including erythema and pain at site of injection, fever, myalgias, and ALT elevation. One intra-tumoral hemorrhage occurred with complete resolution with medical management alone. All patients are alive. CONCLUSION: Poly-ICLC is extremely well tolerated in the NF-1 group and the single agent response rate in this small NF1 cohort is encouraging. Expanded phase II testing of poly-ICLC in the NF-1 cohort is planned.

Aim To examine the association between smoking mentholated cigarettes and smoking cessation, separately for different racial/ethnic groups. Design Secondary data analysis of the 2003 and 2006–07 Tobacco Use Supplements to the Current Population Survey. Setting United States. Participants African American, Asian American/Pacific Islander, Hispanic/Latino, Native American, non-Hispanic white adults. Measurements Examined relations between the use of mentholated cigarettes and measures of smoking cessation. Findings Among African Americans (ORadj = 1.62, 95% CI: 1.35–1.95) and Hispanics/Latinos (ORadj = 1.21, 95% CI: 1.00–1.47), those who currently smoked mentholated cigarettes were more likely be seriously considering quitting in the next six months than were non-menthol smokers, after adjusting for sociodemographic factors. African Americans (ORadj = 1.87, 95% CI: 1.60–2.19) and Hispanics/Latinos (ORadj = 1.34, 95% CI: 1.11–1.62) who smoked mentholated cigarettes were also significantly more likely to have a positive estimation of successfully quitting in the next six months compared to non-menthol smokers. These associations were not found among Asian Americans/Pacific Islanders, Native Americans/Alaska Natives and Non-Hispanic Whites. Among former smokers, across racial/ethnic groups, those who smoked mentholated cigarettes (vs. non-menthols) were significantly less likely to have successfully quit for at least six months: African Americans (ORadj = 0.23, 95% CI: 0.17–0.31), Asian Americans/Pacific Islanders (ORadj = 0.22, 95% CI: 0.11–0.45), Hispanics/Latinos (ORadj = 0.48, 95% CI: 0.34–0.69) and Non-Hispanic Whites (ORadj = 0.28, 95% CI: 0.25–0.33). Conclusion Across race/ethnic groups, those who used to regularly smoke mentholated cigarettes were less likely to have experienced long-term quitting success. Cessation programs should consider the type of cigarette typically smoked by participants, particularly menthols.

Purpose To study the effects of increasing pelvic bone marrow (BM) radiation dose on acute hematologic toxicity in patients undergoing chemoradiotherapy, using a novel modeling approach to preserve the local spatial dose information. Methods and Materials The study included 37 cervical cancer patients treated with concurrent weekly cisplatin and pelvic radiation therapy. The white blood cell count nadir during treatment was used as the indicator for acute hematologic toxicity. Pelvic BM radiation dose distributions were standardized across patients by registering the pelvic BM volumes to a common template, followed by dose remapping using deformable image registration, resulting in a dose array. Principal component (PC) analysis was applied to the dose array, and the significant eigenvectors were identified by linear regression on the PCs. The coefficients for PC regression and significant eigenvectors were represented in three dimensions to identify critical BM subregions where dose accumulation is associated with hematologic toxicity. Results We identified five PCs associated with acute hematologic toxicity. PC analysis regression modeling explained a high proportion of the variation in acute hematologicity (adjusted R 2 , 0.49). Three-dimensional rendering of a linear combination of the significant eigenvectors revealed patterns consistent with anatomical distributions of hematopoietically active BM. Conclusions We have developed a novel approach that preserves spatial dose information to model effects of radiation dose on toxicity, which may be useful in optimizing radiation techniques to avoid critical subregions of normal tissues. Further validation of this approach in a large cohort is ongoing.

Objectives. We aimed to investigate population-level changes in smoking initiation during California's Tobacco Control (CTC) Program from 1990 to 2005, a period during which tobacco industry marketing practices also changed. Methods. We used a discrete time survival analysis of data from the California Tobacco Survey to model changes in age of first smoking experimentation across birth cohorts. Results. Smoking initiation patterns were stable across cohorts aged 9 years or older at the start of the CTC program. For children entering preadolescence since 1990, initiation declined with each more recent cohort. By 2005, the observed decline in experimentation was 80% for male participants and 92% for female participants at age 12 to 14 years; by age 15 to 17 years, 10% of Californian adolescents had experimented in 2005 compared with 45% in preprogram cohorts. However, rates of new experimentation after age 17 years did not change, except for a recent increase in late experimentation (after age 20 years) among young adult men. Conclusion. Our models suggest that the CTC program greatly reduced adolescent smoking initiation among younger adolescents. Late experimentation may have recently increased among young adult men in California, coincident with an increase in tobacco industry marketing aimed at young adults.

6033Background: Pembrolizumab (a humanized monoclonal antibody blocking programmed death receptor-1[PD-1]), and cetuximab (a chimeric monoclonal antibody inhibiting epidermal growth factor receptor...

Although improper urethral catheter insertion is a source of preventable injury in male patients, to our knowledge the extent of this problem is not known. We studied the incidence and mechanism of iatrogenic urinary catheter injuries occurring in adult male inpatients at a single institution. We also designed and implemented an intervention to prevent these injuries.This study was performed during a 13-month period. During months 1 through 6 all catheter related injuries in all adult male admissions to a single academic tertiary care center were prospectively tracked. Incidence data were calculated, injury severity was analyzed and the injury mechanism was identified. During month 7 based on injury mechanism data a nursing education program was designed and implemented by urology staff that included basic urological anatomy, urethral catheter insertion techniques and catheter safety. During months 8 through 13 catheter related injuries were again tracked. The incidences before and after intervention were compared.During the pre-intervention period iatrogenic urethral catheter injuries occurred in 14 of 4,310 consecutive adult male admissions, representing an incidence of 3.2 injuries per 1,000 patients. Penile and/or perineal pain occurred in all 14 affected patients (100%) and penile bleeding occurred in 12 (86%). One patient required cystoscopy for catheter placement and 1 experienced recurrent urethral strictures requiring multiple dilations. During the post-intervention period a total of 3 injuries occurred in 4,523 consecutive patients, representing a statistically significant decrease in risk by a factor of 4.9 and an incidence rate of 0.7/1,000 adult male admissions (Fisher's exact test p = 0.006). Of the 3 post-intervention injuries 2 (67%) occurred in the operating room, an area that was not targeted as part of the intervention.Iatrogenic urethral injuries are a substantial source of preventable morbidity in hospitalized male patients. Implementation of a nursing education program may significantly decrease the incidence of iatrogenic urethral injury and, thereby, improve patient safety.

There is considerable suggestive evidence that parents can protect their adolescents from developing problem behaviors if they implement recommended best parenting practices. These include providing appropriate limits on adolescent free time, maintaining a close personal relationship with the adolescent, and negotiating and providing incentives for positive behavior patterns. However, retention of the study samples has limited conclusions that can be drawn from published studies. This randomized controlled trial recruited and randomized a national population sample of 1036 families to an intensive parenting intervention using telephone counseling or to a no-contact control group. At enrollment, eligible families had an eldest child between the ages of 10–13 years. The intervention included an initial training program using a self-help manual with telephone counselor support. Implementation of best parenting practices was encouraged using quarterly telephone contacts and a family management check-up questionnaire. A computer-assisted structured counseling protocol was used to aid parents who needed additional assistance to implement best practices. This, along with a centralized service, enabled implementation of quality control procedures. Assessment of problem behavior is undertaken with repeated telephone interviews of the target adolescents. The study is powered to test whether the intervention encouraging parents to maintain best parenting practices is associated with a reduction of 25% in the incidence of problem behaviors prior to age 18 years and will be tested through a maximum likelihood framework.

PurposeFollowing colonoscopic polypectomy, US Multisociety Task Force (USMSTF) guidelines stratify patients based on risk of subsequent advanced neoplasia (AN) using number, size, and histology of resected polyps, but have only moderate sensitivity and specificity. We hypothesized that a state-of-the-art statistical prediction model might improve identification of patients at high risk of future AN and address these challenges.MethodsData were pooled from seven prospective studies which had follow-up ascertainment of metachronous AN within 3-5years of baseline polypectomy (combined n=8,228). Pooled data were randomly split into training (n=5,483) and validation (n=2,745) sets. A prognostic model was developed using best practices. Two risk cut-points were identified in the training data which achieved a 10 percentage point improvement in sensitivity and specificity, respectively, over current USMSTF guidelines. Clinical benefit of USMSTF versus model-based risk stratification was then estimated using validation data.ResultsThe final model included polyp location, prior polyp history, patient age, and number, size and histology of resected polyps. The first risk cut-point improved sensitivity but with loss of specificity. The second risk cut-point improved specificity without loss of sensitivity (specificity 46.2% model vs. 42.1% guidelines, p&nbsp

Introduction The diversity of human breast cancer subtypes has led to the hypothesis that breast cancer is actually a number of different diseases arising from cells at various stages of differentiation. The elusive nature of the cell(s) of origin thus hampers approaches to eradicate the disease. Methods Clonal cell lines were isolated from primary transgenic polyomavirus middle T (PyVmT) luminal tumors. Mammary cancer stem cell (MaCSC) properties were examined by immunofluorescence, flow cytometry, differentiation assays and in vivo tumorigenesis. Results Clonal cell lines isolated from primary PyVmT mouse mammary luminal tumors can differentiate into luminal, myoepithelial, alveolar and adipocyte lineages. Upon orthotopic injection, progeny of a single cell follow a pattern of progression from ductal carcinoma in situ, to adenoma, adenocarcinoma and epithelial metastasis that recapitulates the transgenic model. Tumors can evolve in vivo from hormone receptor-positive to hormone receptor-negative Her2-positive, or triple negative CD44hi basal-like and claudin-low tumors. Contrary to the current paradigm, we have defined a model in which multiple tumor subtypes can originate from a single multipotent cancer stem cell that undergoes genetic and/or epigenetic evolution during tumor progression. As in human tumors, the more aggressive tumor subtypes express nuclear p53. Tumor cell lines can also be derived from these more advanced tumor subtypes. Conclusions Since the majority of human tumors are of the luminal subtype, understanding the cell of origin of these tumors and how they relate to other tumor subtypes will impact cancer therapy. Analysis of clonal cell lines derived from different tumor subtypes suggests a developmental hierarchy of MaCSCs, which may provide insights into the progression of human breast cancer. Electronic supplementary material The online version of this article (doi:10.1186/s13058-015-0615-y) contains supplementary material, which is available to authorized users.

Observational data show that nonsteroidal anti-inflammatory drug (NSAID) use is associated with a lower rate of breast cancer. We evaluated the effect of etodolac, an FDA-approved NSAID reported to inhibit cyclooxygenase (COX) enzymes and the retinoid X receptor alpha (RXR), on rationally identified potential biomarkers in breast cancer. Patients with resectable breast cancer planned for initial management with surgical resection were enrolled and took 400 mg of etodolac twice daily prior to surgery. Protein and gene expression levels for genes related to COX-2 and RXRα were evaluated in tumor samples from before and after etodolac exposure. Thirty subjects received etodolac and 17 subjects were assayed as contemporaneous or opportunistic controls. After etodolac exposure mean cyclin D1 protein levels, assayed by immunohistochemistry, decreased (P = 0.03). Notably, pre- versus post cyclin D1 gene expression change went from positive to negative with greater duration of etodolac exposure (r = −0.64, P = 0.01). Additionally, etodolac exposure was associated with a significant increase in COX-2 gene expression levels (fold change: 3.25 [95% CI: 1.9, 5.55]) and a trend toward increased β-catenin expression (fold change: 2.03 [95% CI: 0.93, 4.47]). In resectable breast cancer relatively brief exposure to the NSAID etodolac was associated with reduced cyclin D1 protein levels. Effect was also observed on cyclin D1 gene expression with decreasing levels with longer durations of drug exposure. Increased COX-2 gene expression was seen, possibly due to compensatory feedback. These data highlight the utility of even small clinical trials with access to biospecimens for pharmacodynamic studies.

Objective: This study examined whether receipt of outpatient psychiatric services after hospital discharge was associated with reduced risk of readmission. Methods: Treatment records from patients admitted to San Diego County psychiatric hospitals over a one-year period were obtained from the San Diego County Behavioral Health Services electronic health record system. A discrete-time proportional hazards model was used to examine the association of receipt of outpatient psychiatric services with readmission within 30 days of discharge from the index hospitalization. Results: Of the 4,663 patients, 16% were readmitted within 30 days. In an adjusted model, receipt of outpatient therapy after discharge was associated with a greater likelihood of being readmitted (hazard ratio=1.36, 95% confidence interval=1.14-1.67), whereas receipt of case management or medication management was not associated with readmission. Conclusions: The differential risk of readmission by service type suggests a need for studies that explore reasons for an increased risk of readmission with certain types of services.

© 2015 Hussain et al. Nerve degeneration after transection injury decreases intraoperative visibility under white light (WL), complicating surgical repair. We show here that the use of fluorescently labeled nerve binding probe (F-NP41) can improve intraoperative visualization of chronically (up to 9 months) denervated nerves. In a mouse model for the repair of chronically denervated facial nerves, the intraoperative use of fluorescent labeling decreased time to nerve identification by 40% compared to surgeries performed under WL alone. Cumulative functional post-operative recovery was also significantly improved in the fluorescence guided group as determined by quantitatively tracking of the recovery of whisker movement at time intervals for 6 weeks post-repair. To our knowledge, this is the first description of an injectable probe that increases visibility of chronically denervated nerves during surgical repair in live animals. Future translation of this probe may improve functional outcome for patients with chronic denervation undergoing surgical repair.

© 2015 Bastin et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Background Synchronous tumors can be independent primary tumors or a primary-metastatic (clonal) pair, which may have clinical implications. Mutational profiling of tumor DNA is increasingly common in the clinic. We investigated whether mutational profiling can distinguish independent from clonal tumors in breast and other cancers, using a carefully defined test based on the Clonal Likelihood Score (CLS = 100 x # shared high confidence (HC) mutations/ # total HC mutations). Methods Statistical properties of a formal test using the CLS were investigated. A high CLS is evidence in favor of clonality; the test is implemented as a one-sided binomial test of proportions. Test parameters were empirically determined using 16,422 independent breast tumor pairs and 15 primary-metastatic tumor pairs from 10 cancer types using The Cancer Genome Atlas. Results We validated performance of the test with its established parameters, using five published data sets comprising 15,758 known independent tumor pairs (maximum CLS = 4.1%, minimum p-value = 0.48) and 283 known tumor clonal pairs (minimum CLS 13%, maximum pvalue 0.99), supporting independence. A plausible molecular mechanism for the shift from hormone receptor positive to triple negative was identified in the clonal pair. Conclusion We have developed the statistical properties of a carefully defined Clonal Likelihood Score test from mutational profiling of tumor DNA. Under identified conditions, the test appears to reliably distinguish between synchronous tumors of clonal and of independent origin in several cancer types. This approach may have scientific and clinical utility.

Clinical trial AIN503/A5217 investigates whether a period of early treatment with antiretroviral therapy might lower the viral setpoint in subjects recently infected with HIV-1. We consider two statistical issues. First, even under the null hypothesis control arm subjects are more likely than treatment arm subjects to be missing final outcome data because of disease progression. The analysis must adjust for this missing data, or it may be unacceptably biased. Second, comparing outcomes between treatment and control arms at identical times post-randomization gives different information than comparing outcomes at the same amount of time off-therapy, as measured post-randomization. This may make interpretation of results problematic. We formulate the null hypothesis of the study as exchangeability under a time-shift between arms, which we call “time delay” between the study arms. This captures clinically relevant information, and allows us to formalize a two-stage hypothesis test in which stage one is a comparison between arms at identical times post-randomization, and stage two is a comparison between arms at identical times off-therapy, as measured post-randomization. Importantly, within this framework we can show that the two-stage test can be adjusted for the missing data using a simple worst-rank substitution.

Background: Most studies of colorectal cancer (CRC) risk factors pool cases across anatomical sites, though tumor characteristics and embryologic origins differ. Our aim was to conduct a site-stratified (proximal, distal, rectal) case control study of candidate risk factors for CRC. Methods: Our study base was US Veterans with >1 colonoscopy 1999-2011. CRC cases at baseline colonoscopy were identified with the Veterans Affairs Central Cancer Registry. Controls had normal colonoscopy without biopsy, no history of CRC, and no CRC within 3 years of index colonoscopy. Age, sex, race/ethnicity, body mass index (BMI), diabetes, and smoking were considered candidate risk factors. Primary outcome was CRC, stratified by site. Site-specific odds ratios (OR) and 95% confidence intervals (CI) for each risk factor were computed with unadjusted and adjusted multinomial logistic regression models. Results: We identified 21,739 CRC cases and 616,323 normal colonoscopy controls. For cases combined vs. controls, median age was 68 vs. 61 years, 98% vs. 95% were male, median BMI was 27.8 vs. 28.8 kg/m2, 28% vs. 24% had diabetes, and 25% vs. 29% were non-smokers; race/ethnicity was similar. Presence and strength of associations differed by risk factor and CRC site (Table). Smoking was more closely associated with rectal (OR=1.84) than proximal (OR=1.59) or distal cancer (OR=1.50). Diabetes was more closely associated with proximal than distal or rectal cancer (OR=1.28, 1.17 and 1.12, respectively). Blacks had reduced odds for rectal (OR=0.89), but increased odds for distal (OR=1.27) and particularly proximal cancer (OR=1.60) when compared to non-Hispanic whites. For males vs. females, odds of rectal was higher than distal or proximal cancer (OR=2.64, 1.95 and 1.32, respectively). Conclusions: Presence and strength of association of cancer risk factors may differ by CRC site. Site should be a key consideration in future studies of CRC risk. Table 1.Site specific risk factors for 21,739 CRC cases compared to 616,323 normal colonoscopy controlsAnatomic Site of CRC*Proximal (n=7,686)Distal (n=7,036)Rectal (n=7,017)Candidate Risk FactorOR (CI)OR (CI)OR (CI)Age, years†1.100 (1.096-1.103)1.065 (1.062-1.069)‡1.055 (1.051- 1.059)‡§Gender, male vs. female1.318 (1.080-1.608)1.950 (1.538-2.471)‡2.636 (2.006-3.463)‡Race/ethnicityBlack vs. non-Hispanic white1.596 (1.480-1.720)1.270 (1.167-1.381)‡0.886 (0.808-0.971)‡§Hispanic vs. non-Hispanic white1.291 (1.123-1.485)1.531 (1.337-1.753)1.219 (1.053-1.411)§Asian vs. non-Hispanic white0.872 (0.634-1.201)0.917 (0.662-1.272)0.556 (0.371-0.832)BMI, kg/m2†0.994 (0.988-1.000)1.005 (0.999-1.012)‡0.963 (0.957-0.970)‡§Diabetes, yes vs. no1.278 (1.196-1.366)1.170 (1.089-1.257)1.119 (1.038-1.207)‡SmokingCurrent vs. never1.594 (1.476-1.722)1.500 (1.383-1.627)1.837 (1.695-1.992)‡§Former vs. never0.997 (0.926-1.073)1.082 (1.001-1.171)1.085 (0.998-1.119)* Multinomial analyses adjusted for other risk factors, as well as year of colonoscopy, 1999-2011† by one unit increment‡ p Citation Format: Samir Gupta, Ranier Bustamante, Ashley Earles, Maria E. Martinez, Karen Messer, Christina D. Williams, Andrew J. Gawron, Tonya Kaltenbach, Lin Liu. Site specific risk factors for colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 281. doi:10.1158/1538-7445.AM2017-281

TPS6092 Background: The majority of patients with nasopharyngeal carcinoma (NPC) present with locally advanced disease, with a predilection for early systemic dissemination. For patients who develop recurrent and/or metastatic (R/M) NPC, survival is poor. Following first-line platinum-based regimens, there is no well-defined paradigm for subsequent therapies. Inhibition of PD-L1 with Avelumab is an attractive strategy because Epstein-Barr virus (EBV), the primary causative agent in NPC pathogenesis, universally upregulates PD-L1 expression; proposed mechanisms of upregulation include immune resistance via innate (EBV-induced latent membrane protein-1) and adaptive (Interferon-gamma) mechanisms; increased PD-L1 expression is an independent poor prognostic factor for disease-free survival. Methods: Patients with histologically/cytologically confirmed, EBV-related NPC not amenable to curative intent therapy who received ≥1 prior line of systemic therapy for R/M disease are eligible. Patients must be at least 18 years old, ECOG 0-2, willing to undergo tumor biopsy, have adequate organ and marrow function, and no prior therapy with PD-1/PD-L1 inhibitors. 39 patients will be enrolled across 6 sites. Patients will receive Avelumab 10 mg/kg IV on days 1 and 15 of each 28-day cycle. Treatment will continue until disease progression, unacceptable toxicity, investigator/patient decision. A newly obtained tumor specimen is required at enrollment; optional biopsy at time of progression. EBV plasma DNA titers will be evaluated at baseline, during treatment and at progression, using an EBV BamHI-W DNA PCR. Blood samples at baseline and 12 weeks after treatment initiation will be obtained for correlatives. Primary endpoint is overall response rate (ORR; complete and partial responses) at 6 months per RECIST. A two-stage design will reject H0 (ORR 15%) if the observed ORR is ≥30%, α 0.1, β 0.8, required sample size n = 39. Secondary endpoints include duration of response, progression-free and overall survival. Correlative analyses will evaluate PD-L1 expression, T and B-cell subsets, frequency and clonality. The study has accrued 2 of planned 39 patients. NCT02875613. Clinical trial information: NCT02875613.

Importance Surgical innovations disseminate in the absence of coordinated systems to ensure their safe integration into clinical practice, potentially exposing patients to increased risk for medical error. Objective To investigate associations of patient safety with the diffusion of minimally invasive radical prostatectomy (MIRP) resulting from the development of the da Vinci robot. Design, Setting, and Participants A cohort study of 401 325 patients in the Nationwide Inpatient Sample who underwent radical prostatectomy during MIRP diffusion between January 1, 2003, and December 31, 2009. Main Outcomes and Measures We used Agency for Healthcare Research and Quality Patient Safety Indicators (PSIs), which measure processes of care and surgical provider performance. We estimated the prevalence of MIRP among all prostatectomies and compared PSI incidence between MIRP and open radical prostatectomy in each year during the study. We also collected estimates of MIRP incidence attributed to the manufacturer of the da Vinci robot. Results Patients who underwent MIRP were more likely to be white ( P = .004), have fewer comorbidities ( P = .02), and have undergone surgery in higher-income areas ( P = .005). The incidence of MIRP was substantially lower than da Vinci manufacturer estimates. Rapid diffusion onset occurred in 2006, when MIRP accounted for 10.4% (95% CI, 10.2-10.7) of all radical prostatectomies in the United States. In 2005, MIRP was associated with an increased adjusted risk for any PSI (adjusted odds ratio, 2.0; 95% CI, 1.1-3.7; P = .02) vs open radical prostatectomy. Stratification by hospital status demonstrated similar patterns: rapid diffusion onset among teaching hospitals occurred in 2006 (11.7%; 95% CI, 11.3-12.0), with an increased risk for PSI for MIRP in 2005 (adjusted odds ratio, 2.7; 95% CI, 1.4-5.3; P = .004), and onset among nonteaching hospitals occurred in 2008 (27.1%; 95% CI, 26.6-27.7), with an increased but nonsignificant risk for PSI in 2007 (adjusted odds ratio, 2.0; 95% CI, 0.8-5.2; P = .14). Conclusions and Relevance During its initial national diffusion, MIRP was associated with diminished perioperative patient safety. To promote safety and protect patients, the processes by which surgical innovations disseminate into clinical practice require refinement.