tbuckley/cabot-search huggingface dataset:
Association of delays in time to surgery for resectable stage IIIA non-small cell lung cancer with survival.
Authors: Susan E Combs, Katherine Tullio, Nathan A. Pennell
Journal: Journal of Clinical Oncology (2017)

e20056 Background: Delay in time to surgery (TTS) for early stage non-small cell lung cancer (NSCLC) may impact survival; however the effect of delayed TTS for patients with stage IIIA NSCLC is unclear. Methods: Patients with pathologic stage IIIA NSCLC who underwent curative intent resection with documented days from diagnosis to definitive surgery were identified in the National Cancer Database from 2004 to 2012. Patients with surgery on the day of diagnosis or more than 180 days after diagnosis, and those who received pre-operative systemic or radiation therapy were excluded. Association between TTS as a continuous variable by week and month was assessed by cox regression models. Multivariate cox proportional hazard models estimated the mortality risk associated with TTS as a continuous variable with age, sex, race, comorbidity score, pathologic T and N stage. Overall survival (OS) between immediate and delayed groups was estimated by Kaplan-Meier method and log-rank test. Results: Of patients with NSCLC who underwent definitive resection, 16,033 were confirmed to be pathologic stage IIIA. Median follow-up was 25 months, and 61% of patients died with a median survival of 32 months. Median time from diagnosis to surgery was 37 days. Five-year OS for patients with surgery in the first 37 days was 34.7%, compared to 30.1% in patients who had surgery after the first 37 days (p &lt; 0.001). When grouped by increasing weeks of delay, the earliest significant survival difference was noted in patients resected within three weeks of diagnosis, with 5-yr OS of 35.2%, compared to 31.5% for patients treated more than three weeks later (p = 0.002). For each week of additional TTS, the associated risk of mortality increased by 1.2% (HR 1.012, 95% CI 1.007-1.016, p &lt; 0.001) and 5.0% for each month of delay (HR 1.046, 95% CI 1.026-1.065, p &lt; 0.001). In the multivariate model accounting for confounders, the mortality risk associated with delay to surgery increased by 0.75% with each additional week (HR 1.0075, 95% CI 1.003-1.012, p = 0.002). Conclusions: This analysis suggests that delays in time to curative intent resection for patients with stage IIIA NSCLC decreases the 5-year OS and thus the likelihood of cure.
Abstract 3955:PIK3R1loss activates AKT and STAT3 signaling in ovarian cancer
Authors: Xinran LI, Victor CY Mak, Yuan Zhou, Yiling Lu, Annie NY Cheung, Gordon B Mills, Lydia WT Cheung
Journal: Cancer Research (2018)

Abstract The phosphoinositide 3-kinase (PI3K) regulatory subunit p85α is one of the critical gatekeepers of PI3K pathway activation through stabilizing and inhibiting the catalytic subunit p110. p85α is encoded by PIK3R1, which is frequently mutated or deleted in multiple cancer types including ovarian cancer, providing justification of exploring the approaches to target the aberrations. In this study, we observed a spectrum of oncogenic phenotypes in ovarian cancer cells upon knockdown of PIK3R1 in vitro and in vivo, indicating the functional significance of PIK3R1 loss in ovarian cancer. Strikingly, PIK3R1 loss not only led to AKT activation (canonical signaling of PI3K), but also unexpectedly JAK2/STAT3 signaling activation (non-canonical signaling of PI3K). PIK3R1 loss induced translocation of STAT3 into the nucleus, where gene transcription was promoted and thereby the malignant properties. Using in vitro 3D culture spheroid assay, we found that PIK3R1 loss sensitized ovarian cancer cells to AKT inhibitors and JAK2/STAT3 inhibitors. More importantly, the combination of AKT and STAT3 inhibitors resulted in synergistic loss of cell viability. The demonstrated signaling alterations and the associated therapeutic susceptibility downstream of PIK3R1 loss may open new avenue for the treatment of PIK3R1 loss-bearing cancer. [This study was supported by Research Grants Council of the Hong Kong SAR, China, Project No. 27103616] Citation Format: Xinran LI, Victor CY Mak, Yuan Zhou, Yiling Lu, Annie NY Cheung, Gordon B Mills, Lydia WT Cheung. PIK3R1 loss activates AKT and STAT3 signaling in ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3955.
Precision Medicine Approaches When Prostate Cancer Akts Up
Authors: Tian Zhang, Daniel J. George, Andrew J. Armstrong
Journal: Clinical Cancer Research (2018)

Ipatasertib combined with abiraterone in PTEN-null prostate cancer improved progression-free survival in a randomized phase II study of patients with metastatic castration-resistant prostate cancer (mCRPC), providing clinical evidence of reciprocal activation between the Akt and androgen receptor (AR) pathways. These data revive the rationale for targeting PTEN loss in prostate cancer.See related article by de Bono et al., p. 928.
Impact of numerical variation, allele burden and mutation length on outcomes in acute myeloid leukemia with fms-like tyrosine kinase receptor-3 internal tandem duplication (FLT3-ITD) mutation.
Authors: Ahmad Ghorab, Keyur Patel, Jorge E. Cortes, Dai Chihara, Allyson Price, Tapan M. Kadia, Farhad Ravandi, Naveen Pemmaraju, Naval Guastad Daver, Courtney Denton Dinardo, Hagop M. Kantarjian, Gautam Borthakur
Journal: Journal of Clinical Oncology (2018)

7023 Background: While high allelic burden is known to be associated with adverse outcomes in FLT3-ITD mutated AML, the impact of numerical variation and insert size on clinical outcome of AML patients (pts) is not well studied. Methods: Analysis included 330 newly diagnosed AML pts with FLT3-ITD mutation diagnosed between 3/1999 and 11/2015. Overall survival (OS) was calculated from the time of diagnosis to death/last follow up time (LFU). Relapse free survival (RFS) was calculated from response to relapse/LFU. Results: Table 1 summarizes patient characteristics, response and OS, RFS according to mutation number, size, allelic burden and stem cell transplantation (SCT). Because of the time frame, only 20% pts had frontline exposure to FLT3 inhibitors. Conclusions: Numerical variation and insert length had no significant impact on outcomes while lower allelic burden, FLT3 inhibitor therapy trended towards better RFS. SCT had a significant favorable impact on both OS and RFS.An expanded contemporary cohort analysis is ongoing. Patient characteristics and outcomes: Characteristics Number; N (%), or Median [range] Response Number; N (%), or Median [range] Age, years 60 [17-88] Treatment Regimen Male 165 (50) With FLT3 inhibitor 67 (20) WBC (x106 /L) 12.2 [0.2-278.2] Without FLT3 inhibitor 263 (80) Hemoglobin (g/dL) 9 [4.1-13.1] Treatment Response Platelets (x109/L) 43 [1-326] Complete Remission (CR) 208 (63) Bone marrow blasts (%) 70 [11-98] CR without platelet recovery 24 (7) Peripheral blast (%) 44 [0-99] SCT 89 (27) Diploid Cytogenetics 240 (73) FLT3-ITD Mutation N Median OS (months) p-value N Median RFS (months) p-value Numerical Variation Single ITD 225 12 0.18 80 6.2 0.88 Multiple (≥ 2) ITD 105 17.3 41 6.1 Allele Burden Low ( < 50%) 271 13.6 0.58 103 6.6 0.06 High (≥50%) 57 9.6 18 4.9 ITD Length (base pair; bp) Short ( < 70 bp) 200 13.7 0.25 69 6.2 0.46 Long (≥70 bp) 72 17.4 28 5.7 Treatment Regimen With FLT3 inhibitor 67 16.3 0.14 24 8.6 0.06 Without FLT3 inhibitor 263 12.4 99 6.1 SCT Yes 89 Not Reached < 0.0001 26 8 0.01 No 241 9.8 97 5.8
Durability of brain metastasis response and overall survival in patients with non-small cell lung cancer (NSCLC) treated with pembrolizumab.
Authors: Sarah B. Goldberg, Scott N. Gettinger, Amit Mahajan, Roy S. Herbst, Anne C. Chiang, Rogerio Lilenbaum, Lucia Jilaveanu, Elin Rowen, Heather Gerrish, Annette Komlo, Wei Wei, Veronica Chiang, Harriet M. Kluger
Journal: Journal of Clinical Oncology (2018)

2009 Background: Pembrolizumab can have significant and durable activity in patients (pts) with advanced NSCLC, however the activity in the central nervous system (CNS) and the long-term benefit in pts with active brain metastases (BrM) have not been well-described. Methods: This is a Phase II trial for pts with NSCLC or melanoma with at least 1 BrM between 5 and 20 mm that is asymptomatic and either untreated or progressing after prior local therapy. For NSCLC pts, cohort 1 is for PD-L1 positive and cohort 2 for PD-L1 negative or unevaluable pts. Pembrolizumab 10mg/kg is administered every 2 weeks. The primary endpoint of this trial is BrM response rate (RR), as determined by modified RECIST (mRECIST) in which brain lesions ≥ 5mm are considered measurable and up to 5 target lesions are allowed. Results: By this interim analysis, 67 pts with advanced NSCLC were screened, and 39 were eligible and treated with pembrolizumab: 34 in cohort 1 and 5 in cohort 2. 12 pts (30.8%) were treated as initial therapy for metastatic disease, 14 (35.9%) had 1 prior systemic therapy, and 13 (33.3%) had 2 or more prior lines of therapy. 10 of 34 pts in cohort 1 had a response in CNS, for a BrM RR of 29.4% (95% CI 15.1-47.5). 7 pts had discordance between CNS and systemic responses (4 with PD in brain and PR in body, and 3 with PR in brain and PD in body). Progression-free survival in the CNS among pts with a BrM response or stable disease was 10.7 months (95% CI 6.6-not reached). Median OS among all pts was 8.9 months (95% CI 6.6-29.7), with 31% of pts living at least 2 years (95% CI 19-51%). No pts in cohort 2 had a BrM response, but 2 of the 5 lived > 1 year. Treatment was well-tolerated, with no neurologic adverse events (AEs) > grade 1 considered related to treatment; the only grade ≥ 3 AE related to treatment in more than 5% of pts was grade 3 pneumonitis in 2 pts. Conclusions: Pembrolizumab can result in durable benefit and long-term survival in patients with untreated BrM from NSCLC, with almost a third of patients living more than 2 years after initiation of therapy. We have demonstrated that a PD-L1 inhibitor can have activity in the CNS and may be a safe and active treatment option for patients with small, asymptomatic BrM. Clinical trial information: NCT02085070.
TCT-312 4-year Clinical Results of a Randomized trial Evaluating the Absorb Bioresorbable Vascular Scaffold vs. Metallic Drug-eluting Stent in de novo Native Coronary Artery Lesions: Data from the ABSORB Japan Trial
Authors: Kengo Tanabe, Ken Kozuma, Takeshi Kimura
Journal: Journal of the American College of Cardiology (2018)
Abstract 14013: The Effect of Mid-life Blood Pressure Change and Anti-Hypertensive Treatment on Subsequent Left Ventricular Mass - A Life Course Approach
Authors: Arjun K Ghosh, Rebecca J Hardy, Darrel P Francis, Nishi Chaturvedi, Denis Pellerin, John Deanfield, Diana Kuh, Jamil Mayet, Alun D Hughes
Journal: Circulation (2012)

Background- Clinical practice focuses on current blood pressure (BP) levels with treatment (HTT) initiation once a threshold is crossed. There is less work relating the effects of previous changes ...
Body composition as predictor of toxicity and outcomes in patients with metastatic non-small cell lung cancer (mNSCLC) receiving nivolumab (Nivo).
Authors: Shlomit Strulov Shachar, Rachel Fried, Itamar Shafran, Mor Tal Moskovitz, Grant Richard Williams, Gil Bar-Sela, Anat Strulov Reiner-Benaim, Mira Wollner
Journal: Journal of Clinical Oncology (2018)

e21010 Background: Low muscle mass is associated with adverse cancer outcomes including increased chemotherapy toxicity and reduced survival, while adiposity is linked to chronic low grade inflammation that may increase cancer risk, progression and metastasis. This study investigates the relationship of body composition indices, including muscle mass and adiposity, with treatment outcomes in patients with mNSCLC receiving immune check-point inhibitor-Nivo. Methods: Pretreatment computerized tomography (CT) images were evaluated for skeletal muscle area (SMA), density (SMD), and adipose tissue at the 3rd lumbar vertebrae. Skeletal muscle index (SMI) (SMA/height2) was calculated. Total adipose tissue (TAT) is the sum of visceral, intermusculscular and subcutaneous tissue. Established cut points were used for sarcopenia and TAT.(Martin, JCO, 2015. Caan, CEBP, 2017). The Kaplan-Meier method was used to estimate median survival times, and univariable Cox regression modeling was used to estimate and compare progression free survival (PFS), duration of response (DoR) and overall survival (OS). Odds ratios were estimated for predicting toxicity and group proportions were compared using Fisher`s Exact test. Results: Metastatic NSCLC patients (N = 78) had CT scans within 45 days of starting Nivo. Mean age was 67 (range 24-88). 67% were sarcopenic. Grade 3-4 toxicities (CTCAE version 4.0) were reported in 15% of sarcopenic vs 0% of non-sarcopenic patients (Fisher`s exact test p-value = 0.046, adjusted OR p-value < 0.0001). Response rate was 28%. PFS and OS were shorter in patients with high TAT (1.9 vs 3.7 months, p = 0.064 and 6.2 vs 9.8 months, p = 0.05 respectively). DoR was shorter in non-sarcopenic pts (10.5 vs 16.6 months, p = 0.049) and patients with high TAT (4.7 vs 13.8 months, p = 0.012, adjusted HR = 37.2, p = 0.009). Conclusions: Body composition indices, including muscle and adipose tissue, were associated with toxicity outcomes and survival in patients receiving immune checkpoint inhibitor-Nivo. Further studies are needed to explore how routinely obtained CT scans can be used to individualize the oncologic treatment plan and appropriate interventions.
Factors predicting molecular testing and its impact on survival in racially diverse patients with advanced, non-small cell lung cancer: A retrospective, population-based analysis using administrative claims data.
Authors: Jennifer L. Ersek, James Thomas Symanowski, Edward S. Kim, Swann Arp Adams, James R. Hébert, Jan Marie Eberth
Journal: Journal of Clinical Oncology (2018)

e18691 Background: Lung cancer is the leading cause of cancer death in South Carolina (SC). Tumor molecular testing (MT) advances led to the development of precision medicine treatments, improving outcomes. However, disparities in MT utilization may exist. We evaluated factors related to MT utilization and the impact of MT on overall survival (OS). Methods: Cases diagnosed with stage IIIB/IV non-small cell lung cancer (NSCLC) between January 1, 2002 and December 31, 2012 and available through the SC Central Cancer Registry were linked to SC State Employee Health Plan and Medicaid administrative claims. Logistic regression (LR) was used to identify predictors of MT. Kaplan-Meier methods were used to estimate survival distributions. Log-rank tests compared survival distributions between groups. Cox proportional hazards modeling was used to assess the impact of demographic and clinical characteristics on survival, while adjusting for covariates. Propensity scores were calculated and included as a covariate in propensity-score adjusted Cox models. Results: 2,266 cases were eligible. In the multivariable LR model, predictors of having ≥1 procedure claim for MT included younger age (p = .008), in-state providers (p = .003), low tumor grade (p = .008), adenocarcinoma histology (p = .015), and diagnosis year 2010 or later (p < .001). OS was longer in patients who received MT (median OS = 13.0 vs. 6.0 months, p < .001). After adjustment, patients with MT had a 43% lower risk of death compared to patients without MT (HR = 0.57, 95% CI: 0.40-0.81, p = .002). Conclusions: Several characteristics were associated with MT utilization. In patients with advanced NSCLC, MT may positively influence survival in the population-based setting.
The clinical outcomes of reclassified erythroleukemia (erythroid/myeloid) as myelodysplastic syndrome per 2017 WHO guideline compared to de novo MDS.
Authors: Omar Alkharabsheh, Aref Al-Kali, Salwa Shihadeh Saadeh, Rong He, David Viswanatha, Patricia T. Greipp, Kaaren Reichard, Mithun Vinod Shah, Naseema Gangat, Mrinal Mahesh Patnaik, William J. Hogan, Mark Robert Litzow, Hassan Alkhateeb, Phuong L. Nguyen
Journal: Journal of Clinical Oncology (2018)

e19026 Background: The World Health Organization (WHO) re-visited the diagnostic criteria in 2016 for myeloid malignancies including acute erythroid leukemia (AEL). The former erythroid/myeloid leukemia is now considered as a myelodysplastic syndrome (MDS) if the marrow blasts calculated as a percentage of all bone marrow nucleated cells is < 20%. Aim is to study the clinical outcomes of reclassified erythroid/myeloid leukemia as MDS by WHO 2016 criteria as compared to de novo matched MDS-EB cases. Methods: Retrospective data collection from Mayo Clinic records for patients with confirmed MDS and AEL diagnosis was done. The two groups were combined in one table based on bone marrow blast count (5% to 19%). Cases with therapy related myeloid neoplasms were excluded. Survival estimates were calculated using Kaplan-Meier curves and univariate and multivariate analysis was based on log-rank testing using JMP v.13. Results: Out of 54 AEL patients, 25 who were identified with erythroid/myeloid subtype who met the new 2016 criteria as MDS (group 1), while group (grp) 2 included 388 patients with newly diagnosed MDS (blasts > 4%). Grp1 was younger (median age 64 years vs 69, p = 0.01), had male predominance (grp1: 80%, grp2: 69%), worse cytopenias (hemoglobin 8.4gm/dL vs 9.4 (p = 0.001), WBC 1.8 x109/L vs 2.6 (p = 0.02), platelets 31 x109/L vs 71 (p < 0.001), ANC 690 x109/L vs 1008 (p = 0.05)), and higher blast count (11% vs 9%, p = < 0.001). However, no statistical difference was noted between the 2 grps in R-IPSS cytogenetics (in grp 1: very good 13%, good 39%, intermediate 9%, poor 4% and very poor 35%, and in grp2: very good 3%, good 45%, intermediate 17%, poor 10% and very poor 25%, p = 0.2). The calculated R-IPSS demonstrated a higher risk disease in grp1 compared to grp2 (high and very high 61% vs 37%, p = 0.03). The median overall survival (OS) for grp 1 was 13.9 months and grp 2 was 15.7 months (p = 0.9), and after censoring for BMT; there remained no statistical difference (p = 0.1). Conclusions: Erythroid/myeloid leukemia, reclassified as MDS by WHO 2016, had worse cytopenias, higher blast count and worse IPSS-R compared to newly diagnosed MDS, but despite these differences had similar overall survival.
Initial survival outcomes for the AGITG GAP study – a phase II study of perioperative nab-paclitaxel and gemcitabine for resectable pancreatic ductal adenocarcinoma (PDAC).
Authors: Andrew Barbour, Nicholas O'Rourke, Howard Chan, Yu Jo Chua, James Kench, Rodney J Hicks, Jaswinder S. Samra, Nick Pavlakis, Koroush S Haghighi, Sonia Yip, Mark Donoghoe, Cheryl Friend, Matthew E. Burge, Jonathan Fawcett, Marion Harris, Morteza Aghmesheh, Warren Lance Joubert, Val Gebski, John Simes, David Goldstein
Journal: Journal of Clinical Oncology (2016)

4105 Background: Nab-paclitaxel (nab-PC) and gemcitabine (GEM) are effective for metastatic PDAC. Efficacy of nab-PC and GEM as perioperative chemotherapy (CX) for resectable PDAC is unknown. The GAP trial assessed feasibility and outcomes of preoperative CX in operable PDAC patients (pts). Methods: A multi-centre single arm, phase 2 trial. ECOG 0/1 pts with operable PDAC received 2 cycles of preoperative nab-PC 125mg/m2 and GEM 1000mg/m2on D1, D8, D15 (28 day cycle) and 4 cycles postoperatively if PDAC resected. Response to CX was measured via CT (baseline (BL) and prior surgery) and FDG-PET scans (BL and D15 of cycle 1). Progression–free survival (PFS) defined as period from registration to progression and recurrence-free survival (RFS) is from surgery to relapse. Median follow up for PFS was 27.5 months (mths). Results: 42 pts were enrolled with 39 analysed for response (3 pts excluded – 1 had no PDAC and 2 unresectable at BL), 41 analysed for safety (1 unresectable at BL with no treatment given). The median tumour size was 26mm (IQR 25-35). 93% of pts received nab-PC and GEM preoperatively but only 60% postoperatively. 78% of those pts tolerated adjuvant CX. 5/41 pts did not have surgery (2 progressed, 2 refused, 1 had sepsis). 36 had surgery, of which 6 were unresectable, 1 had no PDAC, 15 had R0 ( > 1mm) resection and 14 had R1 ( < 1mm). PFS (n = 39) was 12.3mths and RFS (n = 28) was 11.7mths (R0 pts 17.7 mths vs R1 pts 10 mths), with 7 pts progression free. 10/39 (26%) pts had a partial response (PR) to neoadjuvant CX while 26 (66%) had stable disease (SD). 15 (48%) had partial metabolic response on PET. Pts with PR on CT were 2.45 times (p = 0.01) more likely to have R0 resection but no correlation was seen with D15 PET response. As per NCCN guidelines at central review 29/39 pts were resectable (7 borderline and 3 unresectable). Median PFS for these pts classed as resectable was 12.3 mths, 21/29 were resected with median RFS 17.2 mths. Conclusions: GAP pts with PR from CX were more likely to have R0 resections and longer RFS. The RFS was similar to previous trials and support use of perioperative CX. Nab-PC and GEM is a well tolerated platform for future studies of preoperative therapy. Clinical trial information: ACTRN12611000848909.
Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) impact on immune microenvironment in non-small cell lung cancer (NSCLC).
Authors: Jie Tang, XiaoLing Liu, Youling Gong, Jiang Zhu, Meijuan Huang, Zhenyu Ding, Min Yu, Yan Tie, Qiu Li, Yongsheng Wang
Journal: Journal of Clinical Oncology (2018)

e21154 Background: EGFR is expressed extensively on epithelial cells, some of stromal cells and even immune cells. However, little is known about systemic impact of EGFR-TKIs on patients with NSCLC and received TKIs treatment. Here we investigated immunological changes and effects on occurred in patients and mice models exposed in EGFR-TKIs. Methods: In order to identify serum biomarkers associated with EGFR-TKIs treatment, we examined 22 samples of NSCLC patients’ serum cytokines at the time of baseline and progressive disease (PD) by cytokine antibody array. C57BL/6 mice (n = 6/group, repeated 3 times) were randomized to Control, Erlotinib (50 mg/kg qd, i.g, 8 weeks), Osimertinib (5 mg/kg qd i.g, 8 weeks), and Afatinib (15 mg/kg qd i.g, 8 weeks). Using flow cytometry, we examined changes of immune cell subsets. Myeloid-derived suppressor cells were analyzed dynamically. Gene expression profile of MDSC and lung tissue were analyzed using RNA Sequencing. Results: Compare to baseline, five cytokines CCL11, CCL15, CXCL7, HGF, GM-CSF were significantly increased in serum of patients achieved PD which associated with MDSC recruitment and expansion. PMN-MDSC accumulation was found in mice bone marrow and spleen in EGFR-TKIs treatment group. Twenty-five immune-related genes expression were significantly increased in EGFR-TKI group (FDR adjusted p < 0.05), such as S100A8 and S100A9 which associated with poor survival in lung adenocarcinoma. In lung tissue from EGFR-TKI-treated mice ,31 immune-related genes differentially expressed. IHC assay manifested the prevalence of PD-L1 expression on alveolar epithelial cells and vascular endothelium was 11% for Control, 72% for Erlotinib, 83% for Afatinib, 44% for Osimertinib. Conclusions: The immune cells and immune microenvironment were changed following EGFR-TKIs treatment. Our study may provide another explanation for poor response to anti-PD-1 or PD-L1 therapy in NSCLC patients with disease progression following EGFR-TKI therapy. Further studies are currently ongoing for testing the elimination of MDSC combining with anti-PD-1 therapy following EGFR-TKI treatment.
P7 LOSS OF KIAA1462, A CORONARY ARTERY DISEASE ASSOCIATED GENE, DECREASES ATHEROSCLEROSIS
Authors: Gillian Douglas, Theodosios Kyriakou, Victoria S Rashbrook, Edward Drydale, Ayman Al Haj Zen, Lucy Trelfa, Vedanta Mehta, Ellie Tzima, Hugh Watkins, Keith M Channon
Journal: Cardiovascular Research (2018)