tbuckley/cabot-search huggingface dataset:
Dissecting the prognostic role of common EGFR-mutations of metastatic NSCLC in TKI era: A systematic review and subgroup meta-analysis.
Authors: Feng-Che Kuan, Liang-Tseng Kuo, Wei-Hsun Yang, Chung-Sheng Shi, Min-Chi Chen, John W. C. Chang, Cheng-Ta Yang, Kuan-Der Lee
Journal: Journal of Clinical Oncology (2018)

9079 Background: Del19 is a good prognostic factor comparing to L858R regarding progression-free survival (PFS). In TKI era, whether Del19 is also good prognostic factor in overall survival (OS) and these two common mutations respond equally to reversible and irreversible TKIs are not elucidated. Methods: A systematic review and subgroup meta-analysis was undertaken to explore the differential efficacy toward frontline reversible and irreversible TKIs between the common mutations. Extracted overall response rate (ORR), PFS or OS were expressed in risk ratio (RR) or hazard ratio (HR) by random-effects model. The pooling of survival curves was expressed in median and interquartile range (IQR). Results: From inception to December 30, 2017, total 20 randomized controlled trials (RCT) and 21 retrospective cohort studies (RCS), comprising of 3,380 patients with Del19 and 2,687 patients with L858R were included in this analysis. Under first-generation (1G) TKIs, Del19 had better ORR, PFS and OS (RRDel19/L858R= 1.19, 95% CI: 1.10-1.28; PFS HRDel19/L858R= 1.25, 95% CI: 1.14-1.37; OS HRDel19/L858R= 1.37, 95% CI: 1.19-1.57). Under second-generation (2G) TKIs, Del19 had no significantly better ORR/PFS (RRDel19/L858R= 1.04, 95% CI: 0.94-1.16; HRDel19/L858R= 1.18, 95% CI: 0.99-1.42). Under 1/2G TKIs, Del19 is good prognostic factor for OS (HRDel19/L858R= 1.35, 95% CI: 1.20-1.52). The pooled median PFS of 1G TKIs was 12.53 (IQR: 11.45-13.70) in Del19 and 10.33 months (IQR: 9.51-11.29) in L858R. The pooled median PFS of 2G TKIs was 14.95 (IQR: 12.01-17.69) and 13.55 months (IQR: 11.33-16.31), respectively. In addition, the pooled median OS of 1G TKIs was 29.48 (IQR: 25.88-33.56) in Del19 and 22.95 months (IQR: 20.54-26.32) in L858R. The pooled median OS of 2G TKI was 32.08 (IQR: 27.86-33.40) and 26.63 months (IQR: 21.15-34.14), respectively. Conclusions: In comparison with L858R, Del19 is a good prognostic factor for RR/PFS under 1G TKIs and for OS under 1/2G TKIs. Common mutations respond differently to reversible and irreversible TKIs. Further study targeting on L858R are warranted to fulfill this unmet need in TKI era.
Tumor cell-free DNA copy number instability compared to CA19-9 as an early predictor of response to systemic therapy in pancreatic ductal adenocarcinoma (PDAC).
Authors: Madappa N. Kundranda, Alexander Koenig, Julia Beck, Kirsten Bornemann-Kolatzki, Jessica Coats, Jana Bergelin, Jordan Waypa, William Marvin Mitchell, Howard Urnovitz, Ekkehard SchÃ¼tz, Tomislav Dragovich, Volker Ellenrieder, Glen J. Weiss
Journal: Journal of Clinical Oncology (2017)

e14524 Background: Humoral tumor markers are used clinically for real-time assessment of therapeutic efficacy. In pancreatic ductal adenocarcinoma (PDAC) the predominant marker is CA19-9, which is not expressed by 10 to 30% of patients depending on race. We compared plasma cell-free DNA (cfDNA) copy number based assay with changes in serum CA19-9 levels and radiological responses to predict responses to systemic therapy. Methods: In a laboratory blinded, prospective multicenter pilot study, 40 non-resectable PDAC patients, treated with (m)FOLFIRINOX, CAPIRI, or gemcitabine +/- nab-paclitaxel) are currently enrolled. CA19-9 was determined in the local center’s laboratory. Tumor cfDNA was measured with a copy-number instability (CNI) scoring assay, determined by next generation sequencing in a centralized laboratory. The CNI score assesses the amount of cfDNA with somatic macro-alterations originating from malignant neoplasms. The difference of the values before commencing therapy (baseline) and prior to cycle 2 (either rising or falling) was calculated as a predictor of standardized radiological evaluation of chemotherapeutic efficacy. Results: 37 patients (3 drop-outs) had data for baseline and cycle 2, of which CA19-9 was elevated and evaluable in 29 patients. The direction from baseline to cycle 2 of CA19-9 and CNI scores were in agreement in 18/29 patients. 9 of 11 cases with discordant CNI score and CA19-9 had treatment response data, and CNI correlated with 7/9 (78%); in contrast 7/9 had rising CA19-9, when response was stable disease or better (22% concordance). In the 27 patients with available imaging, CNI predicted better (n = 18) than CA19-9 (n = 10) (p = 0.03 Fisher’s exact). Conclusions: This comparative study on cfDNA versus CA19-9 suggest that cfDNA CNI quantitation is a potentially more reliable blood based marker for early real-time assessment of efficacy in systemic PDAC therapy than CA19-9, compared to standard of care imaging. The better prediction after the first cycle might be due to the very short in vivo half-life of cfDNA ( &lt; 1hr) compared to about one week for CA19-9. These results justify a larger prospective validation trial.
The prognostic value of tumor residuals indicated by surgeon, by radiology or an integrated approach by surgeons' assessment and pre-chemotherapy CT-scan in patients with advanced ovarian cancer: An exploratory analysis of the AGO Study led Intergroup trial AGO-OVAR 12.
Authors: Florian Heitz, Philipp Harter, Elisabeth Avall-Lundqvist, Alexander Reuss, Patricia Pautier, Gennaro Cormio, Nicoletta Colombo, Johanna Hell, Ignace Vergote, Andres Poveda, P. B. Ottevanger, Lars Christian Hanker, Arto Olavi Leminen, Jerome Alexandre, Ulrich Canzler, Jalid Sehouli, Jorn Herrstedt, Bent Fiane, Michael Merger, Andreas Du Bois
Journal: Journal of Clinical Oncology (2017)

5521 Background: Post-OP TR is a strong prognostic factor in AOC; the best prognosis is observed after complete resection (TR0). TR assessment is performed at the end of the surgery and may be exposed to personal bias. Pre-Chemo CT may improve post-OP assessment, however, it may also be prone to findings by post-OP tumor re-growth, tissue repair or scarring. Methods: Pts with FIGO IIB-IV AOC recruited into the double-blind randomized frontline AGO-OVAR12 trial were scheduled for baseline CT before the 1st chemo cycle. SA and RA of TR were compared. Additionally, a measurement of TR integrating both approaches were assessed (IA). For this IA information of surgical and path reports were reviewed by two of the authors. Results: 1355 pts had complete data for all 3 assessment methods. Of 689 pts with TR0 in SA, 497 (72%) and 539 (78%) had also TR0 pre-Chemo (RA and IA), but showed TR&gt;0 in 192 (28%) and 150 pts (22%), respectively. Pts with SA defined TR0 had a similar median PFS of 27.6 mos compared to TR0 defined by RA (27.8 mos) and IA (28.9 mos). Pts with concordant TR0 (SA/ IA and SA/ RA) had a median PFS of 28.9 mos. In contrast, pts with discordant SA TR0 - RA TR&gt;0 or SA TR0 - IA TR&gt;0 showed inferior median PFS of 19.2 mos (HR: 1.89, 95%CI: 1.48-2.40; p&lt;0.0001) and 16.9 mos (HR: 2.02, 95% CI: 1.57- 2.59; p&lt;0.0001), respectively. Pts with concordant TR&gt;0 had an even lower median PFS of 13.5 (SA and IA) and 12.9 mos (SA and RA). PFS of the experimental therapy or placebo dependent if SA, RA or IA were used, will be presented. Conclusions: Pre-Chemo CT provides information separating the group of pts with post-OP TR0 in pts with TR0 and pts with TR&gt; 0 pre-Chemo. The latter group showed PFS values in between those with surgically assessed post-OP TR0 and those with post-OP TR&gt; 0, forming a third prognostic group. Detailed analysis should evaluate to what extend tumor biology, surgical bias, or imperfect imaging contribute to the discrepancies. Integrating all this may lead to better definition of prognostic groups and the need for specific treatment strategies.
Cytotoxic, apoptotic and molecular effects of fucoidan as single agent and in combination with trastuzumab and docetaxel in HER2(+) breast cancer cells.
Authors: Duygu Aygunes, Canfeza Sezgin, Ruchan Uslu, Buket Kosova
Journal: Journal of Clinical Oncology (2015)

e13520 Background: Breast cancer has high mortality rate in women. Drugs like docetaxel and trastuzumab are important in its treatment. However, in recent years supplements have gained importance in the treatment. Fucoidan, a sulfated polysaccharide mainly found in brown algae and seaweed, is a new candidate for therapy because of its anti-tumor activity. In our study, we aimed to determine cytotoxic, apoptotic and molecular effects of fucoidan and its synergistic and/or antagonistic effects in combination with docetaxel and trastuzumab in the HER2(+) breast cancer cell line MDA-MB-231. Methods: We set six groups for study including fucoidan, docetaxel, trastuzumab as single agents, fucoidan-docetaxel and fucoidan-trastuzumab combinations, untreated cells considered as negative control. IC50 value of each agent was obtained with the WST-1 cytotoxicity assay. Apoptosis was determined with the Annexin V, Active Caspase 2-3-8-9 and MitoCapture assays after applying the IC50value of each agent to MDA-MB-231 cell line. Gene expression levels were evaluated by real-time RT-PCR. MCF-10A non-cancerous epithelial breast cell line was used as a control cell line. Results: Both fucoidan-trastuzumab and fucoidan-docetaxel combinations showed higher cytotoxicity compared to untreated controls and the monodose groups of the agents in MDA-MB-231 cells. Besides, higher apoptotic levels were found for combinations. In contrast, no significant difference for cytotoxicity and apoptosis were found between fucoidan treated and untreated MCF-10A cells. At molecular level, APAF1, BAD, BAX, CASP2, CASP3, CASP8, CASP9, CD27, CDKN1, SFN, TGFb1, TP53, TP73, BRCA1, BRCA2, CDKN1C, CDKN2A, CTNNB1, MGMT, RB1, CCND1, JUN and MAPK1 genes changed significantly (p < 0.05) in fucoidan treated HER2 (+) breast ca cells when compared to untreated and monodose groups. Conclusions: As a result, fucoidan is an effective anti-tumor agent as single and in combination with docetaxel and trastuzumab in HER2(+) breast cancers cells. These findings suggest that fucoidan is a candidate natural product for breast cancer combination therapies, though this need to be validated in further studies.
<i>RAS</i> alterations: Next-generation sequencing of 1,526 patients with diverse malignancies reveals prognostic and therapeutic correlates.
Authors: Shumei Kato, Ryosuke Okamura, Gregory A. Daniels, Aaron Goodman, Suzanna Lee, Noor Khalid, Rachel Collier, Manvita Mareboina, Paul Riviere, Theresa J Whitchurch, Paul T. Fanta, Jason K. Sicklick, Razelle Kurzrock
Journal: Journal of Clinical Oncology (2018)

12096 Background: To date, there is no successful strategy to target RAS alterations. To better understand the clinical impact of different RAS abnormalities, we interrogated the genomics of diverse metastatic/recurrent solid cancers. Methods: We evaluated the molecular profiles of 1,526 patients with diverse malignancies for RAS aberrations as well as co-altered genes using clinical grade next-generation sequencing (NGS) (Foundation Medicine) (182 - 406 gene panels). Therapy and clinical outcomes were assessed (NCT02478931). Results: Overall, 23.5% (358/1,526) harbored RAS alterations (KRAS: 19.3%, NRAS: 3.2%, HRAS: 1.1% [N = 1 with both K- and NRAS alterations]). Patients with RAS alterations had shorter overall survival (OS) than RAS wild-type patients: OS (hazard ratio [HR]: 1.24, 95% confidence interval [CI]: 1.03-1.48, P = 0.02) (multivariate analysis). Amongst RAS mutations, KRAS G12V, KRAS G13D, and KRAS amplification had the shortest OS (multivariate analysis, P = 0.004, 0.004, and 0.02). Co-alterations were seen in 96.4% (345/358) of RAS-mutated patients; patients with PI3K signaling pathway or cell cycle-associated co-altered genes had significantly worse OS when compared to patients without such alterations (HR: 1.52, 95% CI: 1.15-2.01, P = 0.004 and HR: 1.99, 95% CI: 1.49-2.67, P < 0.0001 respectively) (multivariate analysis). 293/358 RAS-mutated recurrent/metastatic solid tumors were evaluable for progression-free survival (PFS). Patients treated with matched therapy targeting non-MAPK co-altered signals (N = 124) had a trend towards longer PFS (HR: 0.79, 95% CI: 0.61-1.03, P = 0.07) but OS was not impacted (HR: 0.98; P = 0.92) when compared to patients who received unmatched therapies (N = 143). Conclusions: Across cancers, RAS alterations were independently associated with poor OS, with KRAS G12V, KRAS G13D, and KRAS amplification having the shortest survival. Most RAS-mutated tumors harbored co-altered genes. Therapy that included drugs matched to co-altered genes did not impact survival, suggesting that MAPK is an important resistance pathway even in the presence of other tractable genomic alterations. Clinical trial information: NCT02478931.
Real-world evidence of cardiac hospitalizations in carfilzomib- and non-carfilzomib-treated multiple myeloma patients in the United States.
Authors: Joseph Mikhael, Khalid Mezzi, Karim Iskander, Kenneth Wang, Christopher Kim, Shao Zhu, Megan Braunlin, Winifred A. Werther, Ajai Chari
Journal: Journal of Clinical Oncology (2018)

8043 Background: Approximately 30% of multiple myeloma (MM) patients (pts) are hospitalized for cardiac events after MM diagnosis. Carfilzomib (K), a 2nd generation proteasome inhibitor, was approved to treat MM in 2012. Methods: We conducted a matched retrospective claims-based cohort study of MM pts who initiated K or non-K treatment (tmt) between 2012-2015 using Truven MarketScan. Pts were > 18 yrs and had ≥1 yr baseline (BL) data before MM diagnosis. Line of therapy (LOT) and regimens were identified using drug prescription claims. Index LOT was defined as first K-containing LOT. Pts who received non-K regimens were matched 2:1 to K pts on age, sex, and index LOT. Hospitalizations were identified using diagnosis codes in claims during index LOT. Any cardiac hospitalizations (CH) included new and existing cardiac conditions defined as having a cardiac code (arrhythmia, heart failure, ischemic heart disease, cardiomyopathy, hypertension) as primary/secondary diagnoses on the claim; primary CH (PCH) had a cardiac code as primary diagnosis. Odds ratios (OR) and 95% confidence intervals (CI) were calculated, adjusting for tmt duration and BL conditions. Results: 498 K and 996 non-K pts were identified (median age 61 and 62 yrs, respectively). In both cohorts, 59% were male; 6%, 30%, and 64% were treated in LOT 1, 2, and 3+. Overall, there was no difference in BL cardiac history (84.9% and 84.1%, respectively). Median tmt duration was 105 and 158 days for K- and non-K pts, respectively. 34% of pts in each cohort were hospitalized. Any CH occurred in 16% and 12% of K- and non-K pts. Unadjusted OR (95% CI) for CH in K pts vs non-K pts was 1.47 (1.1–2.0). When adjusted for tmt duration, OR (95% CI) of CH in K pts vs non-K pts was 1.1 (0.8–1.5). Similar hospitalization risks were seen when additionally adjusting for BL conditions. PCH occurred in 2% and 3% of K and non-K pts, respectively (unadjusted OR [95% CI] 0.7 [0.4–1.4]; adjusted OR [95% CI] 0.55 [0.3–1.1]). Conclusions: In real world pts, the risk of cardiac-related hospitalizations during tmt was similar for K- and matched non-K treated pts when adjusted for tmt duration and BL conditions. Selection bias may impact the risk estimates.
Atypia of undetermined significance in thyroid fine-needle aspiration cytology: Clinicopathological predictors of malignancy.
Authors: Soo Kyung Ahn, Kwang yong Kim, So-youn Jung, Min Kyoon Kim, Mineui Hong
Journal: Journal of Clinical Oncology (2018)

e18103 Background: Fine needle aspiration (FNA) is the gold standard testing modality for benign and malignant thyroid nodules. Categorization as atypia of undetermined significance/follicular lesion of undetermined significance (AUS/FLUS) is regarded as diagnostically ambiguous. This study was designed to identify clinical predictors of malignancy in the subset of patients with AUS/FLUS on FNA cytology. Methods: Retrospective study was done on 150 patients who underwent thyroidectomy after initial diagnosis of AUS/FLUS on preoperative FNA cytology between January 2010 and January 2017. All patients underwent total or subtotal thyroidectomy without repeat FNA biopsy or additional diagnostic modality. Results: Among 150 patients, 84 (56%) were confirmed as malignant nodule after surgery. We identified that the presence of preoperative ultrasonographic multifocality (odds ratio [OR] 1.181; 95% confidence interval [CI] 0.495–2.817, p < 0.01) and sonographic suspicion of malignancy (OR 18.622; 95% CI 4.666–74.315, p < 0.01).were shown to be significantly related to malignancy, whereas feature of thyroiditis on preoperative sonogram was associated with a reduced risk of malignancy (OR 0.144; 95% CI 0.046-0.451, p < 0.01). Conclusions: We recommend that surgical resection of thyroid nodules may be considered in patients with AUS/FLUS showing sonographically suspicious of malignancy and those with multiple nodules.
Endothelial pyruvate kinase M2 maintains vascular integrity
Authors: Boa Kim, Cholsoon Jang, Harita Dharaneeswaran, Jian Li, Mohit Bhide, Steven Yang, Kristina Li, Zolt Arany
Journal: Journal of Clinical Investigation (2018)

The M2 isoform of pyruvate kinase (PKM2) is highly expressed in most cancer cells, and has been studied extensively as a driver of oncogenic metabolism. In contrast, the role of PKM2 in nontransformed cells is little studied, and nearly nothing is known of its role, if any, in quiescent cells. We show here that endothelial cells express PKM2 almost exclusively over PKM1. In proliferating endothelial cells, PKM2 is required to suppress p53 and maintain cell cycle progression. In sharp contrast, PKM2 has a strikingly different role in quiescent endothelial cells, where inhibition of PKM2 leads to degeneration of tight junctions and barrier function. Mechanistically, PKM2 regulates barrier function independently of its canonical activity as a pyruvate kinase. Instead, PKM2 suppresses NF-kB and its downstream target, the vascular permeability factor angiopoietin 2. As a consequence, loss of endothelial cell PKM2 in vivo predisposes mice to VEGF-induced vascular leak, and to severe bacteremia and death in response to sepsis. Together, these data demonstrate new roles of PKM2 in quiescent cells, and highlight the need for caution in developing cancer therapies that target PKM2.
The role of transforming growth factor-β1 signaling pathway during the process of angiogenesis induced by chronic stress in colorectal cancer.
Authors: Jie Zhang, Yaotiao Deng, Tingwu Yi, Jie Liu, Lei Deng, Yuqing Wang, Boyan Huang, Xinmei Luo, Shasha He, Yu Jiang
Journal: Journal of Clinical Oncology (2016)

e23005 Background: Chronic stress could induce stress-related hormones (SRHs), a known risk factor for cancer. Among the SRHs, norepinephrine (NE) is considered to be one with the highest potential. Recent evidences have shown that NE could stimulate hypoxia inducible factor-1α (HIF-1α) expression which is associated with vascular endothelial growth factor (VEGF) secretion and tumor angiogenesis. However, the underlying mechanism is poorly understood. Methods: Tumor bearing athymic BALB/c nude mice received chronic restraint stress and were treated with normal saline, bevacizumab (a human monoclonal VEGF-A neutralizing antibody) or β-adrenergic receptor (β-AR) antagonist (propranolol). Tumor volume and vessel densities in tumor tissues were evaluated. HT-29 and SW480 cells were treated with NE, propranolol or the inhibitor of transforming growth factor-β (TGF-β) receptor Type I kinase (Ly2157299) in vitro. Cellular migration and invasion were tested with transwell migration assay and matrigel invasion assay, respectively. TGF-β1 in mice serum and cell culture supernatant was quantified by ELISA. The expression of HIF-1α in HT-29 and SW480 cells were measured by Real time-PCR and Western blot. Results: Chronic restraint stress was demonstrated to attenuate the efficacy of bevacizumab and promote tumor growth and angiogenesis in a colorectal tumor model. Propranolol blocked this effect and inhibited the elevation of TGF-β1 caused by chronic restraint stress or NE. Propranolol and Ly2157199 could block NE-stimulated HT-29 and SW480 cells migration and invasion. Furthermore, we found that NE up-regulated HIF-1α expression, which was reversed by propranolol and Ly2157299. Therefore, β-AR/TGF-β1 signaling/HIF-1α was a critical signaling pathway involved in chronic stress-related tumor angiogenesis. Conclusions: Our results demonstrated the effect of NE on tumor angiogenesis, and the critical role of β-AR and TGF-β1 signaling during this process. In addition, β-AR/TGF-β1 signaling/HIF-1α/VEGF is a potential signaling pathway involved. This study also indicates that psychosocial stress might be a risk factor of anti-angiogenic therapy.
TCT-323 Comparison of the prognostic predictive value of the SYNTAX II and NERS II risk scores in unprotected left main percutaneous coronary intervention
Authors: Fernando Rebollal-Leal, Xacobe Flores-Rios, Gabriel Sanchez- Fernández, Pablo Piñón-Esteban, Guillermo Aldama-López, Ramon Calvino, José Manuel Vázquez Rodríguez
Journal: Journal of the American College of Cardiology (2018)
A feasibility study of electronic geriatric assessment for real-time morbidity evaluation.
Authors: Geetika Bhatt, Craig C. Hofmeister, Yvonne Adeduni Efebera, Don M. Benson, Douglas Weston Sborov, Samantha Mary Jaglowski, Steven Michael Devine, Tanya Marya Wildes, Desiree Jones, Ying Huang, Ashley Elizabeth Rosko
Journal: Journal of Clinical Oncology (2016)

e21523 Background: Comprehensive Geriatric Assessment (CGA) is a multi-disciplinary screening tool that can predict toxicity and survival in cancer patients (pts) and help improve decisions and outcomes in bone marrow transplant (BMT) by identifying frailty. CGA can however be time and resource intensive for incorporation into cancer clinic. Here, we evaluate the feasibility of incorporating a point-of-care electronic GA (eGA) into a hematology clinic. Methods: A pilot prospective study evaluating 10 domains of GA was performed on 99 pts > 18 years (yrs) with plasma cell dyscrasias undergoing BMT at a single center. Pts completed self-administered surveys (SAS) on demographics, function, psychological status, social support, falls and nutrition using validated standardized tools and a research coordinator administered Short Physical Performance Battery (SPPB) and Modified Mini Mental Status exam (3MS) at pre (T1 ) and 90-day post-transplant visits (T2 ). All data were captured on iPad using Qualtrics survey software and resulted simultaneously. Feasibility measures included completion rate and times, and retention rate. Significance was calculated using regression coefficient. Results: Median age was 59.5 yrs (range(R) = 36-75). Median completion times were: SAS-19 minutes (min) (R = 10-48), SPPB-7 min (R = 4-30), 3MS-8 min (R = 4-25), eGA-36 min (R = 22-70). In pts > 70 yrs, SAS-27 min (R = 25-32), SPPB-8 min (R = 6-12), 3MS-10 min (R = 10) and eGA-45 min (R = 42-60). No statistical significant correlation with age was noted except for SAS (p = 0.036). IPad software failures necessitated use of computers in 3 cases. No pt refused surveys via iPad; 97% required no assistance. At T2 , 57 pts were assessed; 15 were incomplete due to death (n = 5), no transplant (n = 7), transfer of care (n = 3). Three pts declined T2 participation due to fatigue (n = 1), time constraints (n = 1) and trial discontinuation (n = 1). Overall retention rate was favorably high at 74% despite travels > 100 miles in 28%. Conclusions: eGA is feasible and can be rapidly administered during the pre-transplant evaluation without age barriers. Future incorporation of eGA in cancer clinics may help identify frail populations, predict toxicity and improve clinical outcomes.