tbuckley/cabot-search huggingface dataset:
Abstract 12799: Left Atrial Enlargement is an Independent Risk Factor of Stroke or Systemic Embolism in Atrial Fibrillation Patients: The Fushimi AF Registry
Authors: Yasuhiro Hamatani, Daisuke Takagi, Hisashi Ogawa, Masahiro Esato, Yeong-Hwa Chun, Hiromichi Wada, Koji Hasegawa, Mitsuru Abe, Masaharu Akao
Journal: Circulation (2015)

Introduction: Atrial fibrillation (AF) is a common arrhythmic disorder and increasing significantly. Stroke or systemic embolism (SE) is a devastating complication of AF. Controversy exists regarding whether left atrial enlargement is a risk factor of stroke/SE in AF patients. Hypothesis: Left atrial enlargement might be associated with the incidence of stroke/SE. Methods: The Fushimi AF Registry, a community-based prospective survey, was designed to enroll all of the AF patients in Fushimi-ku, which represented a typical urban community in Japan. We started to enroll patients from March 2011, and follow-up data were available for 2,724 patients by April 2015 (median follow-up period 808 days). Left atrial enlargement (LAE) was diagnosed if the left atrial diameter measured by transthoracic echocardiography was &gt;45 mm. We compared the backgrounds and incidences of events during follow-up period between those with LAE and those without it (non-LAE). Results: Backgrounds and incidences of events between LAE and non-LAE are shown in the Table. LAE group showed higher incidence of stroke/SE during follow-up period, compared with non-LAE group (hazard ratio (HR): 1.81, 95% confidence interval (CI): 1.29-2.57, p&lt;0.01). After adjustment by the components of CHADS2 score and oral anticoagulant prescription, LAE was independently associated with higher risk for stroke/SE (HR: 1.70, 95% CI: 1.20-2.43, p&lt;0.01). This was also the case when we defined cut-off as 40 mm (HR: 1.67, 95% CI: 1.12-2.55, p=0.01), and as 50 mm (HR: 1.58, 95% CI: 1.08-2.29, p=0.02), or we analyzed left atrial diameter as continuous variables (HR (per 1mm): 1.03, 95% CI: 1.01-1.05, p&lt;0.01). Even after adjustment by type of AF (paroxysmal or sustained) and valvular heart diseases, LAE remained to be independently associated with the risk of stroke/SE (HR: 1.57, 95% CI: 1.08-2.31, p=0.02). Conclusion: Left atrial enlargement was independently associated with the increased risk of stroke/SE in AF patients.
Exploring the association between somatic molecular features and tumor mutation burden in 513 non–small-cell lung cancer.
Authors: Chenchen Zhu, Jun Zhao, Qichao Xie, Pingping Dai, Liyun Miao, Shuanying Yang, Renhua Guo, Yan Zhang, Gen Lin, Jiang Liu, Huaxia Yang, Yan-Fang Guan, Ling Yang, Xin Yi, Xuefeng Xia
Journal: Journal of Clinical Oncology (2018)

12101 Background: Tumor mutation burden (TMB) is new clinical marker that predicts responses to immunotherapy, but the molecular basis of TMB is unknown. Understand the association between genomic landscape and TMB may help to a better guidance of immunotherapy. Methods: We performed a retrospective review of 513 non–small-cell lung cancers (NSCLC) patients. Tumor tissues were acquired from initial diagnosis before any drug treatment and sequenced by Next Generation Sequencing (NGS) of 1021 genes. TMB (mutations/Mb) was analyzed as the number of somatic non-synonymous base substitution and indel per Mb in coding region. The top quartile was classified as TMB high. Results: A total of 513 patients had an average TMB of 7.5 mut/Mb. The median TMB was 5.8 mut/Mb (range, 1 to 67.68 mut/Mb). 128 patients were assessed as TMB high (TMB-H) and 385 patients were TMB low (TMB-L). The median TMB was 14 and 4.32 mut/Mb for patients with TMB-H and TMB-L respectively. EGFR mutations were detected in 28 patients with TMB-H (21.9%) compared with 228 with TMB-L (59.2%; P < 0.01). And other known drivers were significantly more common in patients with TMB-L than with TMB-H, which included ALK fusion, ROS1 fusion, MET splice and BRAF V600E (P < 0.01). KRAS and TP53 mutations were more common in patients with TMB-H than with TMB-L, but no significant difference of KRAS mutations were found between TMB-H and TMB-L (12.5% vs 7.8%; P = 0.15). Significant differences of TP53 mutations were found between TMB-H and TMB-L (81.3% vs 54.8%; P < 0.01). In addition, alterations of homologous recombination repair and mismatch repair gene were more likely to be the high TMB, e.g. alterations in BRCA1, BRCA2, ATM, ATR, PMS2 and MSH2 were significantly enriched in patients with TMB-H. Conclusions: TMB-H is associated with lack of current druggable oncogenic drivers, such as EGFR mutations/ ALK or ROS1 fusion. TMB detection provides a clinically useful predictor of response to immunotherapy. TP53 and KRAS mutations specifically enriched in patients with TMB-H, may be served as potential predictive factors in guiding immunotherapy. Lastly, DNA damage repair mutations strongly correlated with high TMB, and may be a primary molecular mechanism for TMB.
Epidemiology, clinicopathological features and treatment outcomes of young adults with colorectal cancer in a Brazilian institution: The AC Camargo Cancer Center experience.
Authors: Marcello Ferretti Fanelli, Victor Hugo Fonseca Jesus, Ludmilla T. D. Chinen, Taynan Ribeiro
Journal: Journal of Clinical Oncology (2016)

e15065 Background: Recently, a rising necessity to study cancer in young adults (YA) has emerged. Colorectal cancer (CRC) seldom arises in this population, but when it does, it seems to be associated with a poor prognosis. Reasons remain largely elusive and work is needed to better understand the behaviour of the disease in this subgroup of patients. Methods: Patients aged 19-29 y/o diagnosed with CRC from Jan 2007 to Dec 2012 at AC Camargo were enrolled. A retrospective chart review was performed to collect data regarding epidemiological, clinicopathological and treatment outcome variables. This study has been approved by the local ethics committee. Descriptive statistics were used to describe the clinical features of the population. Survival was calculated using the Kaplan-Meier method. Results: Thirty eight patients were enrolled. Median age was 26 years. Twenty patients were female. Hereditary cancer syndrome was identified in 6 patients and a positive family history of cancer in 22. Most tumor were located in the rectum (18 cases). Seventeen patients had metastatic disease at presentation. Among 19 tumors tested for KRAS, in 13 the result was wild type. Data on treatment outcome were available for 33 patients. After a median follow up of 53.1 months, 15 patients died. Median overall survival was 62.2 months. Among 20 patients with localized disease, 5 experienced disease relapse. Median relapse-free survival has not been reached by now. Median overall survival for patients with localized disease was 72.6 months. Eighteen patients developed metastatic disease (either at presentation or during follow up). Fifteen patients died, with a median overall survival of 17.7 months. All 13 patients with synchronous metastatic disease are dead, with a median survival of 11.2 months. All deaths were cancer- or treatment-related. Conclusions: Metastatic CRC in the YA population carries a poor prognosis, specially in those with synchronous metastasis. Prognosis of localized disease does not seem to be different from the older adult population. Efforts need to be done on identifying the causes of such dismal prognosis in order to improve treatment outcomes.
Serum tumor markers to predict cancer-related venous thromboembolism in gastric cancer.
Authors: Yan Yang, Yang Yang, Jie Shen, Xia Jie, Lixia Yu, Hanqing Qian, Jia Wei, Juan Du, Baorui Liu
Journal: Journal of Clinical Oncology (2017)

e15526 Background: To investigate the relationship between the preoperative level of serum tumor markers and cancer-related venous thromboembolism in patients with gastric cancer. Methods: 1005 patients with gastric cancer who underwent curative resection were finally enrolled in this study. Serum tumor markers including CEA, CA19-9, CA242, CA72-4, CA125 were tested within one week before curative surgery. Measurement data between groups were compared with t test. The sensitivity, specificity, positive predictive values, and negative predictive values of five biomarkers and the combination group were calculated, respectively. The odds ratios were calculated via both univariate and multivariate logistic regression models. Results: Cancer-related venous thromboembolism was found in 540 (53.73%) patients. The increase of each cancer marker is remarkably related with cancer-related venous thromboembolism. The more abnormal serum tumor markers come out, the high the risk of positive cancer-related venous thromboembolism can be. The possibility of positive cancer-related venous thromboembolism would be 2.9 times as much as a normal patient as any of the tumor markers increases. With the increase of any 4 of the tumor markers can make the risk 16.4 times Conclusions: The status of postoperative cancer-related venous thromboembolism can be predicted from preoperative serum tumor markers. For those patients with a high risk of positive cancer-related venous thromboembolism, more aggressive treatment should be arranged.
What is the prognostic impact of <i>BRAF</i> mutation in patients undergoing resection of colorectal liver metastases? Results of nationwide intergroup (ACHBT, FRENCH, AGEO) cohort of 249 patients.
Authors: Jean-Baptiste Bachet, Nathan Moreno-Lopez, Luca Viganò, Ugo Marchese, Maximiliano Gelli, Loic Raoux, Stephanie Truant, Christophe Laurent, Astrid Herrero, Bertrand Le Roy, Sophie Deguelte Lardiere, Guillaume Passot, Vincent Hautefeuille, Christelle De La Fouchardiere, Pascal Artru, Tchalla Ameto, Antoine Brouquet, Antonio Sa Cunha, Stéphane Benoist
Journal: Journal of Clinical Oncology (2018)

3554 Background: BRAF mutation is associated with poor prognosis in patients with metastatic colorectal cancer. In patients with resectable colorectal liver metastases (CRLM), the prognostic impact of BRAF mutation is unknown and the benefit of surgery is debated. This study aims to evaluate oncologic outcome of patients undergoing liver resection for BRAF-mutated CRLM. Methods: From 2012 to 2016, 66 patients underwent resection for BRAF-mutated LM in 24 centers. Case-matched comparison was made with 183 patients who underwent resection for BRAF wild-type CRLM during the same period. The matching criteria were: synchronous or metachronous CRLM, initially resectable or unresectable CRLM, uni- or bilobar distribution, and number (≤ or > 4) of CRLM. Patients with extra-hepatic disease were excluded. Results: Mean follow up was 28.7 ± 19.8 months after surgery. The 1- and 3-year disease-free survival (DFS) rates were 46.1% and 19.3% in BRAF-mutated and 55.4% and 27.8% in BRAF wild-type patients (p = 0.430). In multivariate analysis, BRAF mutation was not a predictor of worse DFS (p = 0.574, OR: 1.12 95%CI: 0.74-1.71). The 1- and 3-year overall survival rates after surgery were 93.5% and 54.3% in BRAF-mutated and 95.8% and 82.9% in BRAF wild-type patients (p = 0.004). The median survival after disease progression was 23.0 months (11-34.9) in BRAF-mutated and 44.3 months (35.9-52.6) in BRAF wild-type patients (p = 0.049). Multisite disease progression was more common in BRAF-mutated than in BRAF wild-type patients (48 vs 30%, p = 0.034) and was less likely to be surgically treated with curative intent (27% vs 42%, p = 0.085). Conclusions: Our results support the interest of surgical therapy of BRAF-mutated resectable CRLM as BRAF mutation by itself does not increase the risk of relapse after surgery. By analogy to non-metastatic CRC, BRAF mutation has a negative impact on survival in patients who relapse after resection of LM.
Abstract 18052: Concentric Tissue Geometry Decreases the Likelihood of Inducing Reentrant Spiral Waves
Authors: Jared M Molitoris, Rajesh B Sekar, Leslie Tung
Journal: Circulation (2016)

Introduction: The anisotropic structure of the heart leads to directional differences in conduction velocity that can be important in the initiation and maintenance of reentrant tachyarrhythmias. H...
Impact of expression of SIRT1 and SIRT2 on outcome in the very elderly patients with colorectal cancer.
Authors: In Sook Woo, Yun Hwa Jung, In Kyu Lee
Journal: Journal of Clinical Oncology (2017)

e15107 Background: Surtuins(SIRTs), NAD + -dependent deacetylases, participate in cell metabolism and ageing associated diseases including cancer. The elderly has higher cancer incidence and mortality compared to the young. Many of patients with colorectal cancer are over the age of 80. The role of SIRT 1 and 2 in tumorigenesis remains debated and it has not been reported for the very elderly patients with cancer. We investigated the relationship of clinicopathologic parameters and expression of SIRT1 and 2 in colorectal cancer patients 80 years of age or older and the impact of ageing comparing with the younger patients. Methods: The expression of SIRT1 and 2 were evaluated in colorectal cancer tissues of 101 patients aged ≥80 years and 29 patients aged ≤40 years by immunohistochemistry. And correlations between expression of these proteins and clinicopathological features were analyzed. Results: High expression of SIRT1 was observed in 65/101 (64.4%) elderly patients and 11/29 (37.9%) young patients(p = 0.011). Similarly, high expression of SIRT2 was more commonly observed in 58/99 (58.6%) elderly patients than 8/29 (27.6%) young patients(p = 0.003). In all patients high SIRT2 expression was associated with comorbid DM, and stage of CRC were not associated with SIRT1 or SIRT2 expression status. Comparison of Kaplan-Meier survival curve using log rank test revealed that high expressions of SIRT1 and SIRT2 were significantly associated with worse prognosis (median OS 24.9ms vs 38.6ms, p = 0.027) and better prognosis (median OS 37.9ms vs 17.3ms, p = 0.006) respectively in elderly patients. No prognostic significances were observed in younger patients. In multivariate analysis, only high SIRT1 expression retained statistical significance as a poor prognostic factor in elderly patients with CRC. Conclusions: :High SIRT1 expression might become a significant poor prognostic factor for elderly CRC patients although further study is needed for younger patients to clarify the difference of expression according to the age between elderly and young patients with CRC. High SIRT2 expression showed association with comorbid DM, further studies are warranted to establish prognostic significance in CRC patients.
Interrogating PI3K to induce PD-L1 expression in oral carcinoma.
Authors: Sanjay Chandrasekaran, Maiko Sasaki, Brian P. Pollack
Journal: Journal of Clinical Oncology (2018)

e24119 Background: PD-L1 expression in oral squamous cell carcinoma (oSCC) is well characterized and is one potential mechanism for suppression of the anti-tumor immune response. Enhanced phosphoinositide 3-kinase (PI3K)/AKT pathway signaling is another hallmark of oSCC, but its ability to alter the immune response to cytokines is not entirely known. We explored the effect of PI3K activation on PD-L1 expression in the presence of interferon-gamma (IFN-g). Methods: HPV-negative SqCC/Y1 oSCC cells were treated with a PTEN inhibitor VO-OHpic and small molecule AKT activator SC79 in the presence of escalating doses of interferon-gamma (IFN-g). Flow cytometry was utilized to evaluate the effect of PI3K activation on PD-L1, MHC I, and MHC II. Correlative studies with PI3K inhibitor pictilisib and dual PI3K & mTOR inhibitor dactolisib were performed. Western blots for AKT, phospho-AKT (p-AKT), and interferon regulatory factor (IRF-1), a known regulator of PD-L1 and MHC, were performed. Clinical correlates utilizing immunohistochemistry (IHC) on human oral cancers were conducted. Results: We demonstrate that both VO-OHpic and SC79 enhance PD-L1 induction by IFN-g and repress MHC I & II. PI3K inhibition with pictilisib conversely repressed PD-L1 and enhanced MHC I & II. Western blots showed increased p-AKT with PI3K activation and increased IRF-1 with PI3K inhibition. IHC in patient biopsy samples showed an inverse relationship between phospho-S6 and MHC I expression. Conclusions: Using small molecule modulators of PI3K signaling, we demonstrate that the PI3K pathway can play opposing roles in the induction of PD-L1 and MHC I by IFN-g in oral squamous carcinoma cells. Further studies in other epithelial cancers and clinical correlates are warranted.
Overall survival based on oncologist density in the United States: Do we need to redefine underserved areas for oncologic care?
Authors: Kathan Mehta, Sudeep Siddappa Malleshappa, Smit Patel, Tapan Mehta, Smith Giri, Leonard Joseph Appleman, Vida Almario Passero, Rahul Atul Parikh
Journal: Journal of Clinical Oncology (2018)

6568 Background: ASCO has predicted shortage of 2,550 to 4,080 oncologists by 2020, disproportionately higher in underserved areas. The Conrad-30 program was established for international medical graduates, trained on J1 visas, to work in medically underserved areas (MUAs) and health professional shortage areas (HPSAs) to correct this disparity. Thirty spots per year are available for each state and primary care providers (PCP) are given priority. The designation of an area as MUA or HPSA is based on shortage of PCPs but not specialists. Methods: We evaluated the impact of oncologist density (OD) defined as number of oncologists per 100,000 (100K) population on overall survival and concordance with MUA or HPSA designation of areas by quartiles of OD. We studied the distribution of oncologists on visa in areas by quartiles of OD by merging SEER data with AMA physician’s master file using Federal Information Processing Standards (FIPS) code of the area. Results: We identified 68,791 adult patients with newly diagnosed hematologic malignancies or metastatic solid cancers (excluding CNS cancers and patients with CNS mets) in 612 FIPS code areas captured by SEER in 2011. After controlling for confounders, compared to patients in areas with lowest quartile of OD ( < 2.9 oncologists per 100K population), patients in areas with 2nd, 3rd and 4th quartile (2.9-6.5, 6.5-8.4, > 8.4 oncologists per 100K population respectively) of OD had better overall survival (HR 0.96, p = 0.001; HR 0.93, p < 0.001; HR 0.9, p < 0.001 respectively). There was no difference in proportion of MUA or HPSA designated areas among the four quartiles (79.6%, 71.9%, 64.5%, and 76.5% from 1st to 4th quartile, p = 0.1). There was no difference in proportion of oncologists working on visa among the 4 quartiles of OD (7.2%, 4.9%, 6.4%, and 6.4% from 1st to 4th quartile, p = 0.5). Conclusions: Patients in areas with higher OD have better overall survival. MUA or HPSA designation is not concordant with OD in different FIPS code areas. The Conrad-30 program is not promoting placement of oncologists on visa in areas with low OD. The Conrad-30 program should be amended to create designated spots for oncologists in each state proportionate to underserved population.
Clinicopathological features and response to platinum-based chemotherapy (PBC) in pancreatic neuroendocrine carcinoma (pNEC): Updated results of Japan pNEC study.
Authors: Nobumasa Mizuno, Waki Hosoda, Keitaro Matsuo, Makoto Ueno, Masayuki Furukawa, Hideyuki Yoshitomi, Masafumi Ikeda, Noritoshi Kobayashi, Shoji Nakamori, Hiroshi Ishii, Yuzo Kodama, Chigusa Morizane, Hiroaki Yanagimoto, Kei Yane, Yoshiaki Tsuchiya, Kenji Notohara, Junji Furuse, Yasushi Yatabe, Susumu Hijioka
Journal: Journal of Clinical Oncology (2016)

e15652 Background: The WHO classified pancreatic neuroendocrine Neoplasms (pNEN) in 2010 as G1, G2, and NEC. However, pNEC is suspected to include heterogeneous disease entities, but is still not fully studied. We aimed to clarify the clinicopathological/molecular characteristics of pNECs. Methods: A total of 100 cases clinical data and pathological slides originally diagnosed as pNEC by the WHO in 2010(WHO-NEC) were retrospectively collected from 31 institutes. Expert pathologists were reassessed all cases slide using the designed protocol and reclassified as well differentiated NET (NET-G3), small cell NEC (SCNEC), and large cell NEC (LCNEC) by morphological features. Results: Thirty cases were eliminated mostly because acinar cell carcinoma, NET-G2 and malignant tumor not otherwise specified, and were eliminated. Remained 70 cases were subclassified into NET-G3 (n = 21, 30%), SCNEC (n = 31, 44.3%), and LCNEC (n = 18, 25.7%). Comparisons of NET-G3 vs. SCNEC vs. LCNEC revealed the following traits: ENETS stage IV (%): 76, 81, 78; median Ki67 LI (%): 28.5 (15–53), 85 (50–100), 70.0 (22–90); abnormal Rb expression (%): 0, 59, 47; KRAS mutations (%): 0, 48, 50; response rate (RR) to PBC (%): 0, 60, 44.4; and overall survival (days): 1255, 196, 340, respectively. When KRAS divided mutation (n = 20) and wild type group (n = 42), RR to PBC as 1st line treatment was 77% vs. 23%. In the same manner, when Rb immune stain divided negative (n = 24) and positive (n = 41), RR to PBC as 1st line treatment was 80% vs. 23.8%. In terms of double abnormalities of Rb expression and KRAS mutation, positive and negative predictive values of response to PBC as 1st line treatment were 100% (7/7, 97.5%CI; 59.0–100) and 69.2% (26/18, 95%CI; 48.2–85.7), respectively. Conclusions: In this retrospective study, WHO-NEC include 30% NET-G3. NET-G3 is clinically and genetically different from SCNEC and LCNEC. As for chemotherapy, Mutated KRAS and/or Rb immunonegativity in tumors with pNEC is associated with response to PBC. Double abnormalities of KRAS mutation and Rb expression may be a strong predictor of PBC.
Aging, Cell Senescence, and Chronic Disease
Authors: Tamara Tchkonia, James L. Kirkland
Journal: JAMA (2018)

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