tbuckley/cabot-search huggingface dataset:
The influences of preoperative metformin on immunological factors in early breast cancer.
Authors: Takahiro Takahiro, Tadahiko Shien, Naruto Taira, Mariko Kochi, Takayuki Iwamoto, Hiroyoshi Doihara, Heiichiro Udono, Shinichi Toyooka
Journal: Journal of Clinical Oncology (2019)

e14182 Background: Metformin is one of the most commonly prescribed drugs for type 2 diabetes, and some reports have suggested that metformin may reduce cancer risk. Diabetics treated with metformin have a 23% reduction in the risk of cancer, including breast cancer. In addition, it is reported that the breast cancer patients with metformin treatment for diabetes showed favorable prognosis compared with those without metformin treatment. However, the mechanism underlying the positive effects of metformin on cancer treatment remains unclear. Methods: We conducted a prospective study to evaluate the effect of preoperative metformin on early breast cancer patients. The patients took a daily dose of metformin orally for 7 to 21 days before surgery. We evaluated the effects on immunological factors (TILs, CD4+, CD8+, PD-L1 and ALDH1) by comparing core needle biopsies (CNB) obtained before surgery with surgical specimens. Results: Seventeen breast cancer patients were enrolled in this prospective study and administered metformin before surgery, during the period from January to December 2016. We analyzed 59 patients who received surgery during the same period as a control group. In the control group, there was no significant difference in TILs between CNB and surgical specimens (Rs = 0.63). In the metformin group, TILs were negative in CNB and surgical specimens of 15 (88%) and 8 (48%) cases, low in 2 (12%) and 8 (48%), and intermediate in 0 and 1 (6%), respectively. These TILs increases were confirmed in 5 (29%) patients (p = 0.09), while a decrease was confirmed in 2 (12%). The expressions of CD4+ and CD8+ by TILs were increased in 41% and 18% of surgical specimens, respectively. (p = 0.02, p = 0.09) However, there was no statistically significant difference in these immunological factors and PD-L1 or ALDH1 expression between before and after metformin. Conclusions: In our small cohort, preoperative metformin administration shows positive impact on CD4 positive lymphocytes significantly and has tendency of increasing both TILs and CD8 positive lymphocytes. However, we should keep in mind that our sample size is small. Further study is necessary to uncover the mechanisms of favorable effects of metformin on breast cancer patients.
Effect of Laparoscopic vs Open Distal Gastrectomy on 3-Year Disease-Free Survival in Patients With Locally Advanced Gastric Cancer
Authors: Jiang Yu, Changming Huang, Yihong Sun, Xiangqian Su, Hui Cao, Jiankun Hu, Kuan Wang, Jian Suo, Kaixiong Tao, Xianli He, Hongbo Wei, Mingang Ying, Weiguo Hu, Xiaohui Du, Yanfeng Hu, Hao Liu, Chaohui Zheng, Ping Li, Jianwei Xie, Fenglin Liu, Ziyu Li, Gang Zhao, Kun Yang, Chunxiao Liu, Haojie Li, Pingyan Chen, Jiafu Ji, Guoxin Li
Journal: JAMA (2019)

<h3>Importance</h3> Laparoscopic distal gastrectomy is accepted as a more effective approach to conventional open distal gastrectomy for early-stage gastric cancer. However, efficacy for locally advanced gastric cancer remains uncertain. <h3>Objective</h3> To compare 3-year disease-free survival for patients with locally advanced gastric cancer after laparoscopic distal gastrectomy or open distal gastrectomy. <h3>Design, Setting, and Patients</h3> The study was a noninferiority, open-label, randomized clinical trial at 14 centers in China. A total of 1056 eligible patients with clinical stage T2, T3, or T4a gastric cancer without bulky nodes or distant metastases were enrolled from September 2012 to December 2014. Final follow-up was on December 31, 2017. <h3>Interventions</h3> Participants were randomized in a 1:1 ratio after stratification by site, age, cancer stage, and histology to undergo either laparoscopic distal gastrectomy (n = 528) or open distal gastrectomy (n = 528) with D2 lymphadenectomy. <h3>Main Outcomes and Measures</h3> The primary end point was 3-year disease-free survival with a noninferiority margin of −10% to compare laparoscopic distal gastrectomy with open distal gastrectomy. Secondary end points of 3-year overall survival and recurrence patterns were tested for superiority. <h3>Results</h3> Among 1056 patients, 1039 (98.4%; mean age, 56.2 years; 313 [30.1%] women) had surgery (laparoscopic distal gastrectomy [n=519] vs open distal gastrectomy [n=520]), and 999 (94.6%) completed the study. Three-year disease-free survival rate was 76.5% in the laparoscopic distal gastrectomy group and 77.8% in the open distal gastrectomy group, absolute difference of −1.3% and a 1-sided 97.5% CI of −6.5% to ∞, not crossing the prespecified noninferiority margin. Three-year overall survival rate (laparoscopic distal gastrectomy vs open distal gastrectomy: 83.1% vs 85.2%; adjusted hazard ratio, 1.19; 95% CI, 0.87 to 1.64;<i>P</i> = .28) and cumulative incidence of recurrence over the 3-year period (laparoscopic distal gastrectomy vs open distal gastrectomy: 18.8% vs 16.5%; subhazard ratio, 1.15; 95% CI, 0.86 to 1.54;<i>P</i> = .35) did not significantly differ between laparoscopic distal gastrectomy and open distal gastrectomy groups. <h3>Conclusions and Relevance</h3> Among patients with a preoperative clinical stage indicating locally advanced gastric cancer, laparoscopic distal gastrectomy, compared with open distal gastrectomy, did not result in inferior disease-free survival at 3 years. <h3>Trial Registration</h3> ClinicalTrials.gov Identifier:NCT01609309
DNA repair deficiency association with prognosis in pancreatic cancer: A single-institution experience.
Authors: Suhaib Bajwa, Thomas A Odeny, Anwaar Saeed, Anup Kasi
Journal: Journal of Clinical Oncology (2019)

e15798 Background: Understanding survival outcomes of various pathogenic mutations helps guide treatment decision making for patients. Classic pancreatic cancer mutations such as KRAS and TP53 have well documented survival outcomes while other mutations leading to DNA repair deficiency do not have well understood survival outcomes. Methods: We retrospectively evaluated survival outcomes of 70 pancreatic cancer patients who had their cancers genetically profiled by NGS methods. Patients with DNA repair deficiency harbored mutations in genes such as BRCA1 (1 Pts), BRCA2 (8 Pts), ATM (5 Pts), NBN (1 Pt), and BRIP1 (1 Pt). We compared baseline characteristics, tumor stage and clinical outcomes between patients with DNA repair deficiency versus DNA repair proficient cancer patients. Comparative survival analysis between the two groups was performed using Kaplan-Meir methods. Results: Baseline characteristics for all patients are recorded in (Table). Median OS is 24 months for DNA repair proficient group and 20 months for DNA repair deficient group. A comparison of Kaplan-Meir survival curves between the two groups yielded a p-value of 0.72. This is most likely due to sample size and different chemotherapy regimens which make it hard to retrospectively compare patient groups. Conclusions: Patients with mutated DNA repair genes did not have significantly worse survival. We are designing a clinical trial utilizing a PARP inhibitor, for these patients in order to better control for all factors in order to better ascertain any survival differences between the two groups. PARP inhibitor will create multiple single strand breaks which cancer cells deficient in DNA repair genes cannot repair and thus trigger cancer cell death[Table: see text]
Implementation of ICH E6 (R2) through identification of data risks using analytics in oncology clinical trials.
Authors: Colin Hayward, Emile Youssef, Melissa Nezos, Debra Jendrasek
Journal: Journal of Clinical Oncology (2019)

e18319 Background: ICH E6 (R2) has increased the level of scrutiny that we have for the data we collect in clinical trials. The emphasis is on quality-by-design with a quality management system to be incorporated and a focus on using a risk-based approach. This can be time-consuming and expensive - though the goal of this addendum is to improve quality AND efficiency, whilst ensuring patient safety and integrity of trial results. We therefore, piloted a proactive, concise and consistent method for utilizing a risk-based approach with central monitoring. Methods: Our method included 1) identifying risks within our data with 8 standard Key Risk Indicators (KRIs) across different study phases and different therapeutic areas together with 2) an off-the-shelf web-based tool for uniform and efficient review by a team of central monitors to assess which data may need more examination. These 8 KRIs are indicated in the list below, in order of the categories within the TransCelerate Risk Assessment and Categorization Tool: (S)AE rates, Enrollment Rates, Screen Failure Rates, Discontinuation Rate, Protocol Deviation Rates, Overdue Query Rate, Data Latency, and Identification of Potential Fraudulent data. Results: 15 studies were configured with the same KRIs and Visual Analytics; histograms, line- and pie-charts and data tables allowing for interactive data visualization and drill down. This represents research across different Phases 1-3 and observational studies. Based upon qualitative survey analysis from the central monitoring team 5/8 KRIs were found to be extremely valuable to focus on study quality, identifying earlier issues in study conduct for the project teams and Sponsors, while the remaining 3 were less valuable. Conclusions: We Our Risk Management team aims to increase the quality of data and ease of implementation of ICHE6 (R2) by focusing on the areas that matter the most, however identifying those areas and managing those data can sometimes be challenging. Through this innovation we have proven some core KRIs of trials that should be most closely monitored to aid decision making and will continue to evaluate to develop core oncology specific KRIs that will allow a more consistent review of data.
Use of treatment pathways reduce cost and decrease ED utilization and unplanned hospital admissions in patients (pts) with stage II breast cancer.
Authors: James L. Weese, Corey J. Shamah, Federico Augusto Sanchez, Ana Cristina Perez Moreno, Dorry Mitchell, Thomas Sessa, Jean Gutantes, Carol Huibregtse, Kevin Clement, Anne Marie Barry-Weers, Bock Amy, Marija Bjegovich-Weidman
Journal: Journal of Clinical Oncology (2019)

e12012 Background: VIA Oncology evidence-based pathways have been integrated into our medical oncology workflows since November 2014. Within 3 months, compliance was high for our 42 medical oncologists at 19 sites working with a common EHR with over 85% of pts treated on pathway. The aim of this study was to determine if there was a significant difference in the overall cost of treatment between pts treated on pathway versus off pathway, and whether on pathway pts had a lower rate of ED use and unplanned admissions within 30 days of chemotherapy as required in the new CMS directives. Methods: Newly diagnosed stage 2 breast cancer pts diagnosed between January 1, 2016 to December 31, 2017 were identified from the tumor registry for the system. The VIA database was queried to separate these pts into two groups–those pts who were treated on pathway, and those who were off pathway. The data warehouse was utilized to determine the total charges of adjuvant medical oncology treatment for these pts. In addition, data was extracted for the same groups to determine those pts who sought ED evaluation and or hospital admission within 30 days of chemotherapy treatment. Statistical analysis was performed utilizing Fisher’s exact test to compare proportions and t-test to compare treatment costs and ED/hospitalizations between the on and off pathway groups. Results: During the 2 years, 412 (93%) Stage 2 breast cancer pts were treated on pathway (including clinical trials); 32 (7%) were off pathway. 81% of the on-pathway group were + for ER and/or PR and 17% were HER-2 +; 78% of the off-pathway group were + for ER and/or PR and 38% were HER-2 +. Mean cost for treating the on-pathway group was $111,067 compared to $200,717 for the off-pathway pts (p=0.01). 18.8% of the off-pathway pts were seen in the ED / unplanned admissions and had more multiple visits compared to 12.1% of on-pathway pts within 30 days of chemotherapy (p=0.026). Conclusions: Standardized usage of evidence based pathways can be used successfully across a large number of providers over wide geography. Adherence to pathways results in significant cost savings for each patient, and significant reduction in ED/hospital utilization for on pathway patients.
Associating somatic mutations to clinical outcomes: a pan-cancer study of survival time
Authors: Paul Little, Dan-Yu Lin, Wei Sun
Journal: Genome Medicine (2019)

We developed subclone multiplicity allocation and somatic heterogeneity (SMASH), a new statistical method for intra-tumor heterogeneity (ITH) inference. SMASH is tailored to the purpose of large-scale association studies with one tumor sample per patient. In a pan-cancer study of 14 cancer types, we studied the associations between survival time and ITH quantified by SMASH, together with other features of somatic mutations. Our results show that ITH is associated with survival time in several cancer types and its effect can be modified by other covariates, such as mutation burden. SMASH is available at https://github.com/Sun-lab/SMASH .
Recurrence and survival after robotic-assisted radical hysterectomy (RRH) for early-stage cervical cancer (CC): Experience may matter.
Authors: Christine K. Fitzsimmons, Amanda J. Stephens, Jessica A. Kennard, Madhavi Manyam, Julie W. Pepe, Kayla M. DeCoff, Sarfraz Ahmad, Nathalie Dauphin McKenzie, James Erasmus Kendrick, Robert W. Holloway
Journal: Journal of Clinical Oncology (2019)

5535 Background: The phase III LACC Trial found that minimally invasive surgery (MIS) / radical hysterectomy was inferior to open radical hysterectomy (ORH) with reduced disease-free survival (86% v 96.5%) and a higher disease-specific death rate (DSDR) (4.4% v 0.6%). We evaluated our experience with attention to the learning curve. Methods: Patients (pts) with early-stage CC (4/2007-12/2017) who underwent RRH with a uterine manipulator were evaluated in a contemporaneously maintained database. First 10 learning curve cases per surgeon (Group A) were compared to all subsequent cases (Group B). Inclusion criteria mirrored the LACC trial: &gt; one-year follow-up, adenocarcinoma, adenosquamous, or squamous carcinoma, stage IA2 or IB1 using FIGO 2014 guidelines, and pathologic tumor size (TS) of 4 cm or less. Atypical histologies and lesions &gt; 4 cm were excluded. Study parameters assessed included recurrence free survival (RFS), DSDR, and pattern of recurrence. Results: 144 RRH pts were identified and 90 met inclusion criteria with mean age of 45.6±14.3 years. Exclusions included stage 1A1 without LVSI (n = 13), atypical histology (n = 10), lost to follow-up (n = 13), and occult stage 1B2 (n = 18). 40 pts met Group A and 50 met Group B criteria. Median follow-up was 61±34.3 months (A = 71.5, B = 52.5). The 5-year RFS was 92% (95 CI ±4%) and the DSDR 5.5% (n = 5). There were 7 (7.8%) recurrences with median time to recurrence of 12±8.3 mos. Recurrence in Group A (n = 6, 15%) exceeded Group B (n = 1, 2%), p= 0.025. DSDR was 10% Group A v 2% B ( p= 0.184). The 4.5 yr RFS was 84.8% (95 CI ±7%) in Group A v 98% (95 CI ±3%) in Group B. There were no differences in risk factors for recurrence between A &amp; B (TS &gt; 2 cm, LN (+), adjuvant therapy (AT), and LVSI p&gt; 0.05), except (+) vaginal margin status (A = 10% v B = 0%, p= 0.034). Three recurrences involved carcinomatosis, which may be insufflation related. All recurrent cases had TS &gt; 2 cm and 5 received AT. Conclusions: In this study, recurrence of disease in early-stage CC clustered in the first 10 cases per surgeon and occurred in TS &gt; 2 cm. This data suggests a possible learning curve effect and argues against a uterine manipulator cause. Carcinomatosis may be insufflation related, unique to MIS, and deserves further study.
Cross-sectional imaging utilization for EGFR, EML/ALK, and KRAS mutant non-small cell lung cancer.
Authors: Thomas Bomberger, Elias Kikano, Kai Laukamp, Daniel Arnold Smith, Amit Gupta, Kianoush Ansari-Gilani, Afshin Dowlati, Nikhil H. Ramaiya
Journal: Journal of Clinical Oncology (2019)

e20663 Background: Targeted therapies for specific genotypic subsets of non-small cell lung cancer (NSCLC) patients have had drastic effects on overall survival at all stages. However, the NCCN guidelines have remained relatively static with respect to initial evaluation, staging, response, and imaging surveillance. In this study we evaluated 3 cohorts of patients, two with a specific targetable mutation (EGFR and EML/ALK) and one without a targetable mutation available (KRAS), for cross-sectional imaging utilization in the initial presentation and surveillance of disease. Methods: Retrospective analysis of imaging studies for patients with NSCLC who received treatment and follow-up between 2007 and 2018 was completed. CT, MRI, and PET imaging data were collected from the picture archiving system. Additional clinical data collected included age, race, smoking history, and dates of diagnosis and death. Results: 153 NSCLC patients were identified with positive EGFR (n = 65), EML/ALK (n = 15), or KRAS (n = 73) mutations. Patients averaged an age of 64 at diagnosis, with a distribution of 38% male, 62% female, 29% current smokers, 48% former smokers, and 23% never smokers. Mean duration between date of diagnosis and death for each group was 1099 ± 770 days (EGFR), 1139 ± 924 days (EML/ALK), and 542 ± 602 days (KRAS). Compared to the KRAS group, the EML/ALK group had higher utilization of chest CTs (p = 0.044), pulmonary embolus CTs (p = &lt; 0.001), abdominopelvic CTs (p = 0.004), and PET CTs (p = 0.006). The EGFR group had significantly fewer pulmonary embolus CTs (p = &lt; 0.001) and higher numbers of non-brain MRIs (p = 0.004) compared to the KRAS group, as well as fewer abdominopelvic CTs (p = 0.034) compared to the EML/ALK group. Conclusions: Different genotypes of NSCLC with available targetable mutations show statistically significant differences in cross-sectional imaging utilization compared to those without targetable mutations. [Table: see text]
Cancer Immune Control Dynamics (CICD): A clinical data driven model of systemic immunity.
Authors: Svetomir Markovic, Allan Sprau, Virginia McElroy, Wendy Kay Nevala, Alexey Leontovich, Harold Frisch
Journal: Journal of Clinical Oncology (2019)

e21058 Background: Recent clinical advances in cancer immuno-therapeutics underscore the need for improved understanding of the complex relationship between cancer and the multiple, multi-functional, inter-dependent, cellular and humoral mediators/regulators of the human immune system. This will lead to improvements in the efficacy of existing immune therapies (patient selection; drug combinations) and insight into new therapeutic targets that may significantly reduce the time to new therapeutics discoveries capable of meaningful clinical impacts. Methods: A systems analysis approach (Cancer Immune Control Dynamics, CICD) attempts to identify the differences between systemic immune homeostasis of healthy volunteers versus patients with metastatic malignant melanoma based on serial measurements of a set of conventional peripheral blood biomarkers of immune function (15 cell subsets and 35 cytokines) assessed daily over 7-10 days. The modeling strategy takes aerospace engineering control theory and system identification algorithms to analyze the state of an individual’s immune system based on the biomarkers’ dynamic non-linear oscillatory behaviors. The analysis framework builds on the classical predator-prey equations commonly used to model biological system dynamics. Tens of thousands of biologically possible biomarker interactions are modeled by a set of matrix equations that creates a system interaction model. CICD quantifies the system equations with biomarker values and solves it to measure the interactions. Results: Quantification of thousands of unique biomarker relationships per participant enables classification based on their immune profile rather than their clinical diagnosis and a basis for a visualization of a person’s immunity state. Conclusions: Results provide initial evidence that a model-based analysis of serially collected biomarker data can lead to biological insights into human immunity, of potential benefit in clinical decisions. It is anticipated that CICD-based capabilities will provide tools to specifically address cancer and treatment modulated (immune checkpoint inhibitors) parameters of human immunity, revealing clinically relevant biological interactions.
Vitamin D status and survival in patients with triple negative breast cancer.
Authors: John Khoury, Sruthi Jinna, Ali Sahlieh, Rebecca Chacko, David Macari, Ishmael A. Jaiyesimi, Marianne T. Huben
Journal: Journal of Clinical Oncology (2019)

e18210 Background: Although many studies have investigated the association of blood 25OH-vitamin D (vit-D) levels with breast cancer prognosis, the results have been mixed. It has been suggested that low vit-D concentrations were associated with advanced tumor stage and triple-negative (TNBC) subtype. We retrospectively investigated associations of serum vit-D levels with triple negative breast cancer outcome. Methods: Out of 797 cases of TNBC diagnosed at William Beaumont Hospital between 2006-2017, 163 patients had vit-D level available within 1 year prior to diagnosis. Analyses of vit-D levels was classified by 3 cut points (deficient, &lt; 20.0 ng/mL; insufficient, 20.0-29.9 ng/mL; sufficient, ≥30.0 ng/mL). Primary outcomes are disease free survival (DFS) and overall survival (OS). SPSS statistics 25 software was used to analyze the data. Results: Median age of diagnosis of TNBC was 60. Of these patients 43.6% were diagnosed with stage I, 37.4% at stage II, 4.9% at stage III and 4.9% at stage IV. 47.2% of the patients had sufficient vit-D level prior to diagnosis, 28.2% with insufficient vit-D level and 24.5% with deficient vit-D. Vit-D deficiency was more prevalent in premenopausal than in postmenopausal women (33.3%, 41% and 25.6% in premenopausal women for deficient, insufficient and sufficient levels respectively vs 21.8%, 24.2% and 54% in postmenopausal women). Rates of Vit-D deficiency were not different between early disease and advanced disease (24.3% of patient with stage I-II vs 25% in patients with stage III-IV). Median OS and disease-free survival were not statistically different among the 3 different categories. 5-year OS was 91%, 91% and 85% for deficient, insufficient and sufficient levels respectively. 5-year DFS was 93%, 95% and 95% for deficient, insufficient and sufficient levels respectively. Multivariate COX regression analysis demonstrated that age and stage were associated with mortality, whereas vit-D level was not. Conclusions: The results from this study show that adequate vit-D level do not have an impact on OS and DFS in patients with triple negative breast cancer. Premenopausal women are more likely to have inadequate vit-D level. Identification and treatment of vitamin D deficiency is still important for musculoskeletal health and possibly extraskeletal health in general population and breast cancer survivors specifically.