tbuckley/cabot-search huggingface dataset:
Is uterine cancer screening indicated or possible in high risk special populations?
Authors: Susan Lee, Anquilla Delaveux, Claud Crosby, Yiju Amy Chen, Kareem Khozaim, Lee Buenconsejo, Ianeta Timoteo, Roland Matthews, Giuseppe Del Priore
Journal: Journal of Clinical Oncology (2019)

e17126 Background: Uterine cancer (UC) is being considered for screening by the CDC due to its relative ascendancy in incidence. We sought to determine its potential for screening using a vanguard of contemporary cancer risk with high non-communicable disease rates (American Samoa [AS]) as a model sample set, and then Grady Hospital (GH) as a test population for screening. Methods: Public access de-identified databases covering the entire national population of AS over several time periods and de-identified GH tumor registry data. Results: In 2014 AS reported 258 new cancers (9.4/10,000 women/yr) including UC (36%), breast (37.6%), cervix (6.6%), ovary (5.1%), and others (14.7%). UC was the leading cause of gynecologic deaths (1.6x &gt; ovarian or cervical). From 2004 - 14 the incidence of UC increased 78.9% to 3.4 cases/10,000 women/yr while breast cancer increased 52.2% to 3.5 cases/10,000. In the most recent 24 months, UC was 2.5x more likely to be diagnosed than breast, 3.6x more than colon, 8x more than cervical and 10.7x more than ovarian cancers. Gyn cancers were the leading cause of cancer death among women after lung. Based on this high incidence of UC, we sought to determine if it would be possible to reach US patients for potential screening using an urban population with health disparities in a test sample of potential beneficiaries of screening for UC the GH Morehouse service (79% black; mean age 58 (33 - 88). From 2010-6, 197 UCs were treated at GH; 96% were GH patients prior to diagnosis with an average time from earliest hospital encounter to the UC diagnosis of 1.75 years (0 – 5.5). Changes from 1 st GH encounter to UC diagnosis and treatment including BMI, age, co-morbidities, etc will be presented. Conclusions: Uterine cancer has similar characteristics to currently screened cancers with an incidence in some high-risk population just under breast and prostate, but ahead of lung and colon. An enriched population, eg. BMI combined with age, especially with disparities, could benefit most from changes in screening strategy and management. Patients with UC are accessible in the hospital of their treatment for potential screening years before diagnosis. This may be an opportunity to reduce cost and morbidity from a rapidly increasing cancer.
A pooled analysis of multicenter cohort studies of post-surgery circulating tumor DNA (ctDNA) in early stage colorectal cancer (CRC).
Authors: Jeanne Tie, Joshua Cohen, Yuxuan Wang, Lu Li, Margaret Lee, Rachel Wong, Suzanne Kosmider, Hui-Li Wong, Belinda Lee, Matthew E. Burge, Desmond Yip, Christos Stelios Karapetis, Timothy Jay Price, Niall C. Tebbutt, Andrew Mark Haydon, Cristian Tomasetti, Nickolas Papadopoulos, Kenneth W. Kinzler, Bert Vogelstein, Peter Gibbs
Journal: Journal of Clinical Oncology (2019)

3518 Background: Studies in multiple tumor types have demonstrated the prognostic impact of ctDNA analysis after curative intent surgery. Emerging data suggest that conversion of ctDNA from detectable to undetectable after adjuvant chemotherapy may reflect treatment efficacy. Further review of existing study data could increase the precision of ctDNA guided adjuvant therapy decision making. Methods: We combined individual patient (pt) data from three independent prospective cohort studies that enrolled 485 pts with stage II or III CRC. Clinicians were blinded to ctDNA results. We evaluated pt outcomes over a 5-year follow-up period (median, 47.2 months). Plasma samples were collected 4 to 10 weeks after surgery. Mutations in ctDNA were assayed using Safe-SeqS. Results: ctDNA was detected after surgery in 59 (12%) pts overall (11.0%, 12.5% and 13.8% respectively for samples taken at 4-6, 6-8 and 8-10 weeks; P = 0.740). ctDNA detection was associated with nodal status; 8.7%, 16.7% and 32.4% in N0, N1 and N2 disease (P &lt; 0.001), but remained an independent adverse prognostic factor in multivariable analysis. ctDNA detection was associated with poor overall survival for pts treated (mortality ratio, 3.0; P = 0.026) or not treated with adjuvant chemotherapy (mortality ratio, 5.17; P &lt; 0.001). The median MAF (mutant allele frequency) in pts with detectable ctDNA was 0.046%. For pts not treated with adjuvant chemotherapy, 3 year recurrence free survival (RFS) was 9% in pts with a MAF &gt; 0.046% vs 33% with a MAF ≤ 0.046% (HR, 2.7; P = 0.032). For chemotherapy treated pts, 3 year RFS was 25% in pts with a MAF &gt; 0.046% vs 70% with a MAF ≤ 0.046 (HR, 3.1; P = 0.025). In 90 pts with recurrence, ctDNA had been detected post surgery in 3 of 20 (15%) with locoregional recurrence, 27 of 60 (45%) with distant recurrence and 5 of 10 (50%) with both (P = 0.044). Conclusions: Where samples for ctDNA analysis were collected 4 to 10 weeks post surgery, sampling timing may not significantly impact detection rates. The prognostic significance of ctDNA detection can be further stratified by MAF level, but MAF level may not impact adjuvant treatment benefit. ctDNA analysis is most sensitive for detecting minimal residual disease at distant sites.
Contributive compared with subsidized insurance in colorectal cancer in the Colombian National Administrative Cancer Registry.
Authors: Robert Hsu, Paula Ramirez, Lizbeth Acuña, Gilberto Lopes
Journal: Journal of Clinical Oncology (2019)

e18136 Background: Colombia has gone to great lengths to provide nearly universal health care insurance for its patients, as 96.6% of its constituents now have health insurance as of 2014 compared to 23.5% in 1993. Most Colombians are associated with either contributive insurance (CI) in which employees and employers contribute to the insurance or subsidized insurance (SI) in which government funds cover the insurance cost. Colorectal cancer (CRC) has the 5 th highest incidence of all malignancies in Colombia. This abstract aims to compare CRC care delivery metrics between CI and SI. Methods: We used the Colombian National Administrative Cancer Registry (NACR) data compiled from the Department of Health Ministry from January 2, 2016- January 1, 2017 consisting of 32 departments and 1122 municipalities. CRC cases were investigated by incidence, mortality, percentage of cases with early stage detection, stage I-III with curative surgery intent, nutritional support, and TNM staging, and days between suspicion to diagnosis, diagnosis to first treatment, neoadjuvant therapy to surgery, and surgery to adjuvant therapy. Results: There were 2605 new CRC cases in the NACR in 2017, with 1691 CI cases and 823 SI cases. There was a noticeably higher incidence in CI (7.2 new cases per 100,000 people) than in SI (3.7 new cases per 100,000), and a higher mortality rate (5.0 deaths per 100,000) in CI compared with SI cases (2.6 deaths per 100,000). There was a significant increase in average wait time for SI CRC cases from diagnosis to first treatment (77.7 days vs. 57.3 days, p = .027) and in average time to neoadjuvant therapy to surgery in CI cases (123.1 days vs. 92.5 days, p = .054) with longer but statistically insignificant wait times in SI cases in average time to adjuvant therapy (83.6 days vs. 73.9 days, p = .0168) and suspicion to diagnosis (56.1 days vs. 46.9 days, p = .811). Similar percentages of CI and SI cases had early stage detection (37.2% in SI vs. 34.3% in CI, p = 0.311), TNM staging (50.7% in CI vs. 49.3% in SI, p = 0.146), stage I-III cases with curative surgery intent (23.3% in CI vs. 21.8% in SI, p = 0.833), and nutritional support (10.5% in CI vs. 8.5% in SI, p = 0.942). Conclusions: The NACR represents a model for developing countries to improve cancer care delivery efficiently. As evidenced by higher incidence and mortality in CI cases and longer wait times before treatment in SI cases, there are differences in cancer care delivery between major modes of healthcare delivery in Colombia. More investigation needs to be done with a goal of streamlining cancer care delivery.
KEYNOTE-189: Updated OS and progression after the next line of therapy (PFS2) with pembrolizumab (pembro) plus chemo with pemetrexed and platinum vs placebo plus chemo for metastatic nonsquamous NSCLC.
Authors: Shirish M. Gadgeel, Marina Chiara Garassino, Emilio Esteban, Giovanna Speranza, Enriqueta Felip, Maximilian J. Hochmair, Steven Francis Powell, Susanna Y. Cheng, Helge Bischoff, Nir Peled, Rina Hui, Martin Reck, Takayasu Kurata, Edward B. Garon, Michael J. Boyer, Jing Yang, Maria Catherine Pietanza, Delvys Rodriguez-Abreu
Journal: Journal of Clinical Oncology (2019)

9013 Background: Pembro + chemo significantly improved OS and PFS over chemo alone and had manageable safety as 1L therapy for metastatic nonsquamous NSCLC in the KEYNOTE-189 study (NCT02578680). The benefit was observed irrespective of PD-L1 TPS. We present updated OS based on longer follow-up and, for the first time, PFS2. Methods: Eligible pts were randomized 2:1 to pembro (n = 410) or placebo (n = 206) + pemetrexed and carboplatin or cisplatin for 4 cycles followed by pembro or placebo for up to 35 cycles + maintenance pemetrexed. Pts in the chemo arm could crossover to pembro alone upon PD. Poststudy anticancer therapy and outcomes were collected. PFS2 was defined as time from randomization to PD per investigator after start of 2L therapy or death, whichever occurred first. There was no multiplicity adjustment, and all P values are nominal. Data cutoff was 21 Sep 2018. Results: With 18.7-mo median follow-up, pembro + chemo continued to provide longer OS (HR 0.56 [95% CI 0.45-0.70], P &lt; .00001; median 22.0 mo vs 10.7 mo) and PFS (HR 0.48 [95% CI 0.40-0.58], P &lt; .00001). Benefit was seen in all PD-L1 TPS groups (Table). 2L+ therapy was received by 45% in the pembro + chemo arm and 59% (54% 2L+ immunotherapy) in the placebo + chemo arm. PFS2 was longer for 1L pembro + chemo (HR 0.49 [95% CI 0.40-0.59], P &lt; .00001; median 17.0 mo vs 9.0 mo), with no difference by TPS (Table). Conclusions: 1L pembro + pemetrexed/platinum continued to show substantial OS benefit in metastatic nonsquamous NSCLC, regardless of PD-L1 TPS and despite 54% of pts in the placebo + chemo arm receiving subsequent immunotherapy. Median OS, PFS and PFS2 were approximately doubled with pembro + chemo. These data confirm that pembro should be given as part of 1L therapy to maximize outcomes in both PD-L1expressing and PD-L1non-expressing NSCLC. Clinical trial information: NCT02578680. [Table: see text]
Effects of SM08502, a novel, oral small-molecule inhibitor of Wnt pathway signaling, on gene expression and antitumor activity in colorectal cancer (CRC) models.
Authors: Carine Bossard, Kevin Chiu, Heekyung Chung, John Duc Nguyen, Emily Creger, Brian Eastman, Chi Ching Mak, Long Do, Shawn Cho, Sunil KC, Timothy Phalen, Jeyanesh Tambiah, Steven Cha
Journal: Journal of Clinical Oncology (2019)

e15185 Background: Aberrant activation of Wnt signaling contributing to tumorigenesis is most commonly associated with CRC (90% harbor Wnt pathway mutations). SM08502, a novel, oral Wnt signaling pathway inhibitor, was evaluated in preclinical CRC models. Methods: In vitro Wnt signaling: assessed using TOPflash β-catenin/TCF reporter assay in SW480 human CRC cells. In vitro Wnt pathway gene expression: measured by qRT-PCR in SW480 and Wnt3a-stimulated cells (HEK-293T, IEC-6), and with the Nanostring Wnt pathway array (180 genes) across a panel of 16 CRC cell lines. In vitro cell proliferation: 17 CRC cell lines were used to test cell viability following treatment. In vivo antitumor activity: Oral SM08502 was tested in CRC mouse xenografts (SW480, HCT 116) and a PDX model over 20-21 days (QD, QOD). 24-hr pharmacodynamic (PD) analysis of Wnt pathway gene expression was done in SW480 tumor explants from mice following one 25 mg/kg dose. Results: SM08502 inhibited Wnt pathway signaling (EC 50 = 46 nM) in SW480 cells. Wnt pathway gene expression was inhibited by SM08502 (0.3-3 µM) in Wnt3a-stimulated cells ( AXIN2, LEF1) and SW480 ( AXIN2, CTNNB1, LEF1, MYC, TCF7, TCF7L2) at 24 hrs ( P &lt; .05 vs. vehicle) . Corresponding effects on protein expression were confirmed for all genes except CTNNB1, suggesting SM08502 acted independently of β-catenin. Nanostring array screening identified inhibition of LRP5, DVL2, BTRC, and ERBB2 by SM08502. Cell proliferation was inhibited in all 17 lines (avg. EC 50 = 177 nM). In vivo, SM08502 was well tolerated and induced dose-dependent antitumor effects in xenografts and PDX models. Tumor growth inhibition for 25 mg/kg QD (max dose) was 83%, 56%, and 70% in SW480, HCT 116, and PDX, respectively. PD analysis showed significant inhibition ( P&lt; .05 vs. vehicle) of TCF7, MYC, LRP5, DVL2, and BTRC expression 8 hrs post treatment. Conclusions: In preclinical CRC models, SM08502 was a potent inhibitor of Wnt pathway signaling and gene expression. It showed strong antitumor activity in human tumor models with activating Wnt pathway mutations. The safety, tolerability, and PK of SM08502 are being evaluated in an ongoing phase 1 study (NCT03355066).
Deployment and integration of a cognitive technology in China: Experiences and lessons learned.
Authors: Tianle Li, Cheng Chen, Shan-shan Zhang, Irene Dankwa-Mullan, Alan Chen, Anita Preininger, Gretchen Purcell Jackson, Jun Liang
Journal: Journal of Clinical Oncology (2019)

6538 Background: Cognitive technologies are rapidly being introduced in oncology for decision-support, prescribing therapy, predicting risk, reducing medical errors and for care management. Few studies have reported on successful approaches for clinical adoption. We report the early adopter experience of BahealIntelligenceTechnologyCo., Ltd. (Baheal), across China within a 2-year period (April 2017-January 2019). We also describe lessons and experiences of oncology users. Methods: Baheal developed collaborative agreements for use of IBM Watson for Oncology (WFO) in 96 hospitals across 8 provinces. Key opinion leaders who saw the potential for AI were recruited as champion advocates. A 29-item survey conducted included usability and integration within clinical workflow. 85 questionnaires were distributed to oncologists who were major WfO users; 51 were completed. All questionnaires were completed anonymously and de-identified prior to analysis. Results: As of January 31, 2019, 866 physicians have entered a total of 52,537 cancer cases into WfO. Most users approved of both the quality (44/51, 86.3%) and comprehensibility (45/51, 88.2%) of treatment options, rationales, and literature references. WfO was most frequently applied in the context of inpatient cases reviewed by a multidisciplinary tumor board (MDT) (44/51, 86.3%). A lack of locally available treatments in WfO was cited as an area for improvement by two-thirds of users (34/51, 66.7%). CDS was rated from 0 (lowest) to 10 (highest) for each of the following uses: EBM medical education (8.1); assistance with literature (7.7); medical care quality control (7.3); second opinion consultations (7.0); case review with tumor board (6.9); and decision support (6.4). Overall, users were willing to recommend CDS to patients and other clinicians (7.3). Conclusions: WfO CDS, employed in a variety of settings, was viewed positively by more than 86% of users, with perceived benefits differing by context. Future incorporation of locally available treatments and understanding reasons for their omission in CDS may increase perceived value, improve standardization, quality of cancer care and equity of care in China.
Expanded access for cancer patients: The 5-year FDA CBER experience.
Authors: Laronna S. Colbert, Peter F. Bross, Ke Liu
Journal: Journal of Clinical Oncology (2019)

e18158 Background: Expanded access (EA) refers to the use of an investigational drug when the primary purpose is to diagnose, monitor, or treat a patient’s disease rather than to generate scientific data that is generally derived from clinical trials. FDA has long facilitated expanded access to investigational drugs for patients with serious or immediately life-threatening diseases and who lack therapeutic alternatives. EA requests include single-patient use protocols under existing INDs, single-patient investigational new drug applications (INDs or SPIs), and intermediate-size or treatment protocols/INDs. Methods: We searched the Center for Biologics Evaluation and Research (CBER) internal databases and reviewed all EA requests for cancer patients to receive investigational products regulated by CBER's Office of Tissues and Advanced Therapies (OTAT) from 2014-2018. These products included cellular and gene therapies, cancer vaccines and microbe-based therapies. Results: From 2014-2018, OTAT received 395 EA requests for solid tumor (ST) or hematologic malignancies (HM). One-hundred ninety-seven (197) requests were for individuals who could not be enrolled in an ongoing oncology clinical trial to receive an investigational agent (single-patient use protocols). Of 197 requests, 7 (3%) were either withdrawn or canceled by the treating physicians (sponsors). The remaining 190 (100%) were approved. One hundred seventy-three (173) EA requests, 102 for ST and 71 for HM, came from sponsors to make available to patients an investigational agent for which there were no ongoing clinical trials (SPIs). Of 173 requests, 45 (26%) were withdrawn or cancelled by the sponsors. Of the remaining 128, 127 (99%) were approved. One request was denied. Twenty-five of 395 EA requests were for intermediate-size or treatment protocols/INDs. Conclusions: From 2014-2018 there has been an increase in oncology EA requests for products regulated by CBER/OTAT, which pose unique challenges for evaluating their risks and benefits. Despite the complexities of these novel biological products, nearly all EA requests were approved.
Mutational burden on circulating cell-free tumor-DNA testing as a surrogate marker of mismatch repair deficiency/microsatellite instability and/or response to immunotherapy in patients with colorectal cancer.
Authors: Saivaishnavi Kamatham, Dorin Colibaseanu, Amit Merchea, Faisal Shahjehan, Jason Scott Starr, Kabir Mody, Pashtoon Murtaza Kasi
Journal: Journal of Clinical Oncology (2019)

e15066 Background: Circulating cell-free tumor-DNA (ctDNA) testing (‘liquid biopsy’) is increasingly being employed both in clinical trials as well as clinical practice. We aimed to contrast and compare the differences in the number of somatic mutations observed on ctDNA testing between mismatch repair deficient/microsatellite instability-high (dMMR/MSI-High) versus mismatch repair proficient/microsatellite stable (pMMR/MSS) colorectal cancers (CRC). Methods: We had 20 patients at Mayo Clinic Florida that were dMMR/MSI-High with testing through the commercially available platform (Guardant360) that uses a 73-gene panel. Median numbers of somatic mutations were compared between the 2 subset of CRC. Results: Patients with dMMR/MSI-High CRC had a median of 8 mutations (range: 2-15) versus a median of 4 mutations (range: 1-22) in pMMR/MSS patients, p-value of 0.001. Similarly, the mean number of somatic mutations were 7.47 (S.D. ± 4.15) versus 5.02 mutations (S.D. ± 3.83) in patients with dMMR/MSI-H and pMMR/MSS, tumors respectively. Though it is simplistic, we could still potentially identify patients who may be candidates for immunotherapy by gauging the mutational burden reported (Table). Furthermore, on serial testing, decline in mutational burden as early as few weeks into therapy was predictive of response later on imaging. Conclusions: Analysis of number of somatic mutations on ctDNA testing can be complementary to MMR/MSI-testing, especially in situations when tissue is not available or safe to obtain. This can also be of value in predicting and/or following response to immunotherapy. The utility of this may go beyond CRC in identifying patients who may benefit from immunotherapy. [Table: see text]
Deep learning and alternative learning strategies for retrospective real-world clinical data
Authors: David Chen, Sijia Liu, Paul Kingsbury, Sunghwan Sohn, Curtis B. Storlie, Elizabeth B. Habermann, James M. Naessens, David W. Larson, Hongfang Liu
Journal: npj Digital Medicine (2019)

Abstract In recent years, there is increasing enthusiasm in the healthcare research community for artificial intelligence to provide big data analytics and augment decision making. One of the prime reasons for this is the enormous impact of deep learning for utilization of complex healthcare big data. Although deep learning is a powerful analytic tool for the complex data contained in electronic health records (EHRs), there are also limitations which can make the choice of deep learning inferior in some healthcare applications. In this paper, we give a brief overview of the limitations of deep learning illustrated through case studies done over the years aiming to promote the consideration of alternative analytic strategies for healthcare.
High-throughput single-cell ChIP-seq identifies heterogeneity of chromatin states in breast cancer
Authors: Kevin Grosselin, Adeline Durand, Justine Marsolier, Adeline Poitou, Elisabetta Marangoni, Fariba Nemati, Ahmed Dahmani, Sonia Lameiras, Fabien Reyal, Olivia Frenoy, Yannick Pousse, Marcel Reichen, Adam Woolfe, Colin Brenan, Andrew D. Griffiths, Céline Vallot, Annabelle Gérard
Journal: Nature Genetics (2019)
Fecal Incontinence Diagnosed by the Rome IV Criteria in the United States, Canada, and the United Kingdom
Authors: William E. Whitehead, Magnus Simren, Jan Busby-Whitehead, Steve Heymen, Miranda A.L. van Tilburg, Ami D. Sperber, Olafur S. Palsson
Journal: Clinical Gastroenterology and Hepatology (2019)
A Decade Later, Lessons Learned From the Hospital Readmissions Reduction Program
Authors: Andrew M. Ibrahim, Justin B. Dimick
Journal: JAMA Network Open (2019)

Ashwin Ramaswamy, BA; Maya Marchese, MS; Alexander P. Cole, MD; Sabrina Harmouch, MD; David Friedlander, MD, MPH; Joel S. Weissman, PhD; Stuart R. Lipsitz, ScD; Adil H. Haider, MD; Adam S. Kibel, MD; Andrew J. Schoenfeld, MD, MSc; Quoc-Dien Trinh, MD