tbuckley/cabot-search huggingface dataset:
Programmed cell death receptor ligand 1 (PD-L1) expression: Epidermal growth factor receptor (<i>EGFR)</i> and <i>Kirsten RAS</i> (KRAS) mutations in second-line therapy (2L) non-small cell lung cancer (NSCLC) patients—A Danish cohort study.
Authors: Deirdre Cronin-Fenton, Tapashi Dalvi, Elizabeth Hedgeman, Mette Nørgaard, Lars Pedersen, Hanh Hansen, Jon Fryzek, David Lawrence, Jill Walker, Anders Mellemgaard, Torben Riis Rasmussen, Norah Shire, James R. Rigas, Danielle Potter, Stephen Hamilton-Dutoit, Henrik Toft Sørensen
Journal: Journal of Clinical Oncology (2017)

e20523 Background: In NSCLC patients who received 2L therapy, we examined the association of PD-L1 expression, mutations in KRAS and EGFR and survival. Methods: 2L NSCLC patients diagnosed during 2001-2012 and with sufficient archival tumour tissue were selected from the Danish Lung Cancer Group Registry. We retrieved patient data from population-based medical registries, and paraffin-embedded tumor tissue from pathology archives. We assessed PD-L1 expression using the Ventana IHC (SP263) validated assay (using 25% cutoff for positivity), and genotyped KRAS and EGFR via PCR-based kits. Follow-up was from the start of 2L therapy to death, emigration, or 31/12/2014. We used Cox regression to compute hazard ratios (HR) and associated 95% confidence intervals (95%CI) for PD-L1, EGFR and KRAS. Results: Among 368 patients, 204 (55%) were men, 250 (68%) were aged &gt;60 years at diagnosis, and 95% were ever-smokers. 233 (63%) had adenocarcinoma, 90 (24%) had PD-L1 positive tumors, 28 (8%) had EGFR mutations, and 113 (31%) had KRAS mutations. In the PD-L1 positive tumors, 7% had EGFR and 37% KRAS mutations, respectively. In the PD-L1 negative tumors, 9% had EGFR and 32% KRAS mutations, respectively. Patients with KRAS mutations had shorter survival compared with wild-type patients. Survival was longer for patients with EGFR mutations compared with wildtype patients. PD-L1 expression did not correlate with survival (Table). Conclusions: Our findings suggest that EGFR and KRAS mutations, but not PD-L1 expression, correlate with survival in 2L NSCLC patients. [Table: see text]
Lymphocytes and neutrophils count after two cycles and TTF1 expression as early outcome predictors during immunotherapy (IT) in stage IV non-small cell lung cancer (NSCLC) patients.
Authors: Iosune Baraibar, Ricardo Oroz, Marta Roman, Patricia Martin, Mariano Ponz-Sarvisé, Christian Diego Rolfo, José María López-Picazo, Jose Luis Perez-Gracia, Alfonso Gurpide, Pablo Sala Elarre, Ignacio Gil-Bazo
Journal: Journal of Clinical Oncology (2017)

e20553 Background: NSCLC therapeutic paradigm has changed with immune checkpoint blockers. Biomarkers predicting clinical benefit are still lacking. As previously shown in melanoma, changes in absolute lymphocytes and neutrophils count (ALC and ANC) during IT (PD-1/PD-L1 inhibitors) may be related to response in NSCLC (Nakamuta et al, Oncotarget 2016). TTF1 expression has been associated with PD-L1 expression (Vieira et al, Lung Cancer 2016). We aimed to investigate TTF1 expression and changes in ALC and ANC after 2 cycles and their potential association with clinical outcomes to IT. Methods: We retrospectively analyzed 26 consecutive patients with stage IV NSCLC treated with IT at Clínica Universidad de Navarra (Spain) during 2016. Radiological response was evaluated according to RECIST v1.1. The potential correlation between ALC and ANC changes during the first two cycles and response to treatment [disease control rate (DCR) vs progression] was evaluated using Student’s T-test. Fisher’s exact test was used to study the association between changes in ALC ( &lt; 1,000 vs &gt; 1,000) and ANC ( &lt; 4,000 vs &gt; 4,000) after 2 cycles and response to IT. TTF-1 expression was correlated with treatment response. Overall survival (OS) was assessed with Kaplan-Meier analysis and Log-rank test according to ALC and ANC. Results: An ALC increase after 2 cycles was significantly associated with DCR compared to progression (192 vs -155; p = 0.043). ALC &gt; 1,000 after 2 cycles was more frequent among patients experiencing DCR compared to progression (87% vs 50%; p = 0.07). ALC &gt; 1,000 after 2 cycles was more frequently observed among patients with TTF1+ tumors (93% vs 55%; p = 0.03). Patients with ANC &lt; 4,000 showed a longer median OS (NR vs 19.25 months; p = 0.03). TTF1 expression in adenocarcinoma (n = 18) was associated with response to IT (83% vs 16%, p = 0.01). Conclusions: Despite this retrospective small series’ limitations, our results show that ALC and ANC changes during IT and TTF1 expression may act as early predictors of clinical benefit in stage IV NSCLC patients treated with PD1/PD-L1 blockers. Our results warrant further investigation in larger prospective series.
TCT-376 Bioprosthetic Valve Fracture To Improve Hemodynamic Function Following Aortic Valve-in-Valve implantation with CT follow-up
Authors: Abdullah Alenezi, John Webb, Jonathon Leipsic, Philipp Blanke, David Wood, Jonathan Weir-McCall, Dale Murdoch, Janarthanan Sathananthan, Mark Hensey, Abdullah Alkhodair
Journal: Journal of the American College of Cardiology (2018)
Comparison of SUV and RECIST responses in cancers treated with SM-88.
Authors: Dacian V. Bonta, Zachary Gostout, Patricia Zawisny, Maria Loushin, Giuseppe Del Priore
Journal: Journal of Clinical Oncology (2018)

e14528 Background: Recent examples, such as iRECIST for checkpoint inhibitors, have demonstrated that response criteria other than RECIST 1.1 may be more appropriate for some therapeutic mechanisms. SM-88 is a relatively non-toxic novel combination of dysfunctional tyrosine and repurposed agents (CYP3a4 inducer, mTOR inhibitor, plus oxidative stress catalyst) with potential efficacy in multiple cancer types. Because SM-88’s mechanism of action is based on metabolism and the Warburg Effect, standardized uptake values (SUVs) with PET imaging may provide an earlier indication of therapeutic response. Methods: Retrospective chart review identifying patients who had undergone multiple FDG-PET CT exams in proximity to or during treatment with SM-88 (aka SMK). All subjects (n=107) received po SM-88 5 days/week. Combination therapy, with other anti-neoplastics including parenteral SM-88, was permitted amongst the compassionate use cases. Of the 11 evaluable patients, response to therapy was evaluated according to change in tumor size (RECIST 1.1) and SUVmax. Results: Nine patients received SM-88 monotherapy and 2 were combination therapy. Cancers included: breast (n=7), Ewing’s Sarcoma (n=2), thyroid (n=1), and renal (n=1). SM-88 BORRs were 4 CRs, 6 PRs, and 1 SDs (BORR not based exclusively upon scans herein). Mean time between baseline scan and initiation of therapy was less than 1 wk (-9-19) and 18 wks (1-66) for the follow-up scan. At 2nd scan the range in RECIST-based diameter changes was -73% to +13% (-1% median) in comparison to a reduction in SUV of 23% to 100% (48% median). All subjects evaluated had a greater % decrease in SUV than RECIST measurements. 7/11 subjects (64%) had a >30% reduction in SUVmax while 2/11 (18%) had RECIST diameter change>30% (X2 p<.05). SUVmax at 2nd scan showing ≥30% reduction had a 85.7% positive predictive value for best overall response of either a PR or CR RECIST response. Three of the patients that eventually achieved a RECIST CR had a greater % initial drop in SUV than RECIST change. Conclusions: PET-based SUV may provide an early indication of therapeutic activity for metabolically-based cancer treatments. Larger studies of the correlation are required to determine relevance in clinical decision making
P03.02 Ketogenic diets as an adjuvant therapy in glioblastoma (KEATING): A mixed method, randomised, feasibility study.
Authors: K J Martin-McGill, M G Cherry, A G Marson, C Tudur Smith, M D Jenkinson
Journal: Neuro-Oncology (2018)

There is increasing interest in the use of ketogenic diets (KD) as adjuvant therapy for glioblastoma (GBM). This trial aimed to: (i) investigate protocol feasibility, (ii) measure patient and carer tolerability and (iii) inform the design of future phase III clinical trials. A prospective, non-blinded, randomised, feasibility study with an embedded qualitative design assessing recruitment and retention challenges and experiences. Twelve newly diagnosed GBM patients were randomised to the modified ketogenic diet (MKD) or the medium chain triglyceride ketogenic diet (MCT KD). Primary outcome was retention at 12 weeks. Secondary outcomes assessed at 12 weeks and 12 months included recruitment rate, side effects, anthropometric changes, dietary acceptability and long term retention. Semi-structured interviews were conducted with a purposive sample of patients and relatives (n=15), including those who declined, withdrew and retained up until 12 weeks. Recruitment was achieved within the desired timeframe of 12 months. Fifty-seven patients were screened, 42 were eligible to participate and 12 were recruited (29% recruitment rate). Retention was poor; of the 12 patients randomised, 4 completed the 12 week dietary trial, of which 3 followed MCT KD. Median duration on diet was 36.5 days (range 0–49 days) for those who discontinued prior to 12 weeks (n=8). No dietary related serious adverse events occurred. Mean weight loss was 8.51kg (S.D 9.66kg) over 12 weeks (n=4), however this was intentional as all patients were overweight or obese at baseline. Gastrointestinal intolerances occurred at dietary initiation (n=3), resolving by week 6. Those who participated in the study reported their decision to be a ‘gut reaction’, whilst those who declined to participate appeared more considered in their decision, reporting the diet to be too restrictive and too time consuming for the relative to prepare. Whilst relatives did not influence the patient’s decision to participate in the study, all patients sought their relative’s opinion. Participants reported high levels of relative burden and support required when implementing KD. Some underestimated this, resulting in withdrawal. Those who withdrew reported KD to negatively impact their lifestyle. Retainers had a positive experience and reported that the diet became ‘the new normal’. Ketone monitoring was seen as a motivation for retainers, and a burden for withdrawers. Patients reported that the 3-month diet duration was too long but 5–6 weeks to be more attainable. Recruitment to a GBM ketogenic trial is possible. Retention at 3 months was poor due to the diet negatively impacting patients’ lifestyle and causing burden for relatives. To assess efficacy in a stage III trial, a 6 week dietary intervention would be advantageous.
P01.137 Long term follow-up of neuropsychological functions in patients with high grade gliomas: can cognitive status predict survival or tumor recurrence?
Authors: B Zarino, A Di Cristofori, G Abete Fornara, G Bertani, M Locatelli, M Caroli, P Rampini, D Crepaldi, G Carrabba
Journal: Neuro-Oncology (2018)

Patients with high grade gliomas (HGG) have a poor prognosis and experience cognitive deficits which depend on location, size, mass effect and edema of the tumor. Neuropsychological functioning (NPF) can be assessed by a battery of tests which objectivise the cognitive status of the patients. These tests are time-consuming and fatiguing for the patients, nevertheless could give relevant information about the course of the disease. Aim of our work was to describe overtime the NPF of patients affected by HGG and to correlate the NPF scores with tumor recurrence and survival. We examined the NPF in 102 patients operated for HGG. Patients were followed longitudinally with the Milano-Bicocca Battery for neuropsychological assessment of low grade gliomas. Patients were evaluated before surgery and few days after surgery. Then, neuropsychological and neuro-oncological follow-up were performed every three months. We first explored the correlational structure of our neuropsychological variables through hierarchical clustering in the R package Hmisc. We then investigated the impact on patients’ outcome of the variables selected through hierarchical clustering via non-linear regression, with fixed/random effects. Time to tumor recurrence/death was selected as the main dependent variable. Sixty-seven males and 35 females (median age 59, range 18–81) were included. Starting from a battery of 27 neuropsychological tests, 10 tests could be selected from the statistical analysis (cluster structure, condition number K of 51.16) since they were strictly correlated with the other tests; thus, these 10 tests were used for the further statistical analysis. Pitting patients’ neuropsychological profiles against tumor relapse/death, 5 cognitive tests showed a significant correlation: Token test (p=0.003), Object Naming test (p=0.02), Digit Memory Span (p=0.001), Corsi Block test (p=0.004), Semantic Fluency test (p=0.003). A steep decline for all these tests emerged a few weeks before tumor relapse/death. Analyzing the NPF overtime, all the tests worsened immediately after surgery, recovered steadily within 2–3 months and then remained stable until progression. The tests which showed to be more informative about the patients NPF were Token test, Object Naming test, Digit Memory Span, Corsi Block test, Semantic Fluency test. These tests showed a significant decline few weeks before tumor relapse/death.
Epigenetic inactivation of miR-9 in EVI1<sup>high</sup> pediatric AML.
Authors: Nupur Mittal, Liping Li, Zhijian Qian
Journal: Journal of Clinical Oncology (2016)

10537 Background: EVI-1 hyper expression seen in 25% of pediatric AML patients is associated with an inferior prognosis. The role of EVI1-induced aberrant methylation in AML is elusive. Oncogenic roles of miR-9 have been reported in solid tumors. The role of miR-9 in human AML is undetermined. We illustrated a unique role of miR-9 in murine myelopoesis previously. Clinical trials in AML patients have evaluated epigenetic agents, however, whether these drugs can specifically counteract EVI1-mediated leukemogenic activity is unknown. Pediatric experience with these drugs is very limited. Our objective is to determine whether epigenetic inactivation of miR-9 by EVI1 contributes to EVI1high pediatric AML. Methods: AML cell lines (AML-1, Kasumi-3 , U 937) and 38 primary AML pediatric samples were checked for EVI-1 and miR-9 expression by q-RT PCR. Methylation of the CpG enriched miR 9 promoter was evaluated by direct sequencing of bisulfite-converted DNA. Human EVI1high/EVI1low AML cell lines and patient cells were treated with 5-AZA,analyzed for miR-9 expression, growth, apoptosis and colony formation . miR-9 was re-expressed in EVI-1high/EVI1lowcell lines and primary bone marrow cells using lentiviral vector and growth, apoptosis and colony formation were assessed. Results: EVI1 hyperexpression in cell lines and AML patient samples correlates with downregulation of miR-9. There was significantly increased methylation of miR-9 promoter in EVI-1high cell lines (AML-1, Kasumi-3) and patient cells compared to EVI-1low cell line (U 937) and patient cells. miR-9 expression was significantly reactivated by 5-AZA in EVI1high in contrast to EVI1low cell lines. Activation of miR-9 using 5-AZA treatment and re-expression of miR-9 by lentivirus results in significant growth inhibition, increased apoptosis and decreased colony formation in EVI1high cell lines / BM samples but does not affect survival of EVI1lowcell lines, BM samples and control CD 34 cells. Conclusions: Epigenetic inactivation of miR-9 by EVI1 contributes to EVI1high pediatric AML .Forced expression of miR-9 or its reactivation by 5-AZA induces apoptosis and inhibits growth of EVI1high AML cells. miR-9 is a therapeutic target and hypomethylation a potential strategy for EVI1high pediatric AML.
Stereotactic ablative radiation therapy for the treatment of oligometastatic prostate cancer.
Authors: Phuoc T. Tran, C. Leigh Moyer, Ryan Phillips, Noura Radwan, Ashley Ross, Diane K. Reyes, Jean Wright, Emmanuel S. Antonarakis, Daniel Y. Song, Curtiland Deville, Patrick C. Walsh, Theodore L. DeWeese, Michael Anthony Carducci, Edward M. Schaeffer, Kenneth J. Pienta, Mario A. Eisenberger
Journal: Journal of Clinical Oncology (2017)

5020 Background: The importance of local treatment in oligometastatic prostate cancer (OPC) is unknown. Stereotactic ablative radiotherapy (SABR) is highly focused, high-dose radiation that is well suited for treatment of oligometastases. Here we report on the safety and preliminary clinical outcomes of SABR in a modern cohort of OPC men. Methods: Eighty four men who satisfied criteria of OPC diagnosed on imaging underwent consolidative SABR were then followed prospectively on our IRB approved registry by our GU multidisciplinary team. We collected demographic, clinical, toxicity and efficacy information. We examined the first 66 men in this preliminary report to allow for a minimum of 4.5 months follow-up. SABR was delivered in 1-5 fractions of 5-18 Gy. Kaplan-Meier method was used to assess local progression-free survival (LPFS), biochemical progression-free survival (bPFS; PSA nadir+2), distant progression free survival (DPFS), ADT-free survival (ADT-FS) and time-to-next intervention (TTNI). Results: Of the 66 OPC patients analyzed, 25 (38%) men presented as synchronous OPC and the remaining 41 had recurrent OPC. Median and mean follow-up was 61 and 66 weeks, respectively. Patient and disease factors as listed in the Table. Crude Grade 1 and 2 acute toxicities were 36% and 11%, respectively, with no Grade &gt; 2 toxicity. SABR was delivered to 134 metastases: 89 bone (66%), 40 nodal (30%) and 5 (4%) visceral metastases. Overall LPFS at 1-year was 92%. The bPFS and DPFS at 1-year were 69% and 69%, respectively. Median TTNI was not reached yet. Of the 18 men with hormone sensitive prostate cancer who had their ADT deferred, 11/18 (56%) remain free of disease following SABR (1-year ADT-FS was 78%) and in 17 castration resistant men, 11 had &gt; 50% PSA declines with 1-year TTNI of 30% with a median of 45 weeks. Conclusions: Consolidative SABRfor OPCis feasible and well tolerated. The preliminary clinical outcomes in our series is limited by heterogeneity and size but our data suggests that this approach is worthy of further prospective study. [Table: see text]
Breast cancer-related paraneoplastic neurologic disease.
Authors: Brittany L. Murphy, Nicholas L. Zalewski, Amy C. Degnim, Andrew McKeon, Eoin P Flanagan, Sean J. Pittock, Elizabeth B. Habermann
Journal: Journal of Clinical Oncology (2017)

11559 Background: Paraneoplastic neurologic disease (PND) is an aberrant immune-mediated response against the nervous system triggered by occult malignancy. Given the rarity of this disease, a paucity of data exists describing breast cancer (BC)-related PND; thus, we sought to further examine this specific population of patients. Methods: Using an institution specific clinical search tool, we identified all patients at our institution from 1997-2016 with a diagnosis of BC-related PND, verified by an international expert. Retrospective review was used to record tumor and treatment factors associated with PND and BC. A descriptive analysis was performed of the characteristics associated with BC-related PND. Results: BC-related PND was diagnosed in 58 female patients. Average age at BC diagnosis was 54.0±10.3 years. Most had invasive cancer of Stage II or higher [Stage 0 (10.3%), I (10.3%), II (44.8%), III (13.8%), IV (6.9%), unknown (13.8%)]. Most patients were hormone receptor (HR)+ (63.8%), while 4 (6.9%) were HR-, and 17 (29.3%) were unknown. Of the 34 patients where Her2/neu (Her2) data was available, 7 (20.6%) were Her2+ and 27 (79.4%) were Her2-. The majority (62.1%) had neurological symptoms prior to BC, 5.2% were concurrent, and 32.7% developed PND after initial BC. The interquartile range for time from PND to BC diagnosis was -8.5 to 10.5 months. Of the 58 patients, 29 (50%) had autoantibodies detected: Purkinje Cell Cytoplasmic Autoantibody Type-1 (PCA-1[anti-Yo]) (10), amphiphysin-IgG (n = 9), Anti-Neuronal Nuclear Autoantibody Type-2 (ANNA-2[anti-Ri]) (n = 5), and other (n = 5). The most common syndromes were cerebellar ataxia (n = 14), myelopathy (n = 11), and myopathy (n = 11). Immunotherapy was used for PND in 53 of 58 (91.4%) patients; benefit from immunotherapy was assessed as complete 0 (0%), robust 11 (20.8%), mild to moderate 28 (52.8%), none 9 (17%), and indeterminate 5 (9.4%). Conclusions: BC-related PND is rare, with only 58 cases over 20 years at a large academic institution. Paraneoplastic symptoms often present prior to BC diagnosis and BC characteristics are typical of the general population. Over 75% of patients benefit from immunotherapy. These data may provide helpful information to providers treating this population of patients.
Outcomes in patients (pts) who had received sorafenib (S) as the only prior systemic therapy in the phase 3 CELESTIAL trial of cabozantinib (C) versus placebo (P) in advanced hepatocellular carcinoma (HCC).
Authors: Robin Kate Kelley, Baek-Yeol Ryoo, Philippe Merle, Joong-Won Park, Luigi Bolondi, Stephen Lam Chan, Ho Yeong Lim, Ari David Baron, Francis Parnis, Jennifer Knox, Stéphane Cattan, Thomas Cheung Yau, Julie Lougheed, Steven Milwee, Anthony El-Khoueiry, Ann-Lii Cheng, Tim Meyer, Ghassan K. Abou-Alfa
Journal: Journal of Clinical Oncology (2018)

4088 Background: C inhibits tyrosine kinases including MET, VEGFR, and AXL. In the CELESTIAL trial, C improved overall survival (OS) and progression-free survival (PFS) compared with P in pts with advanced HCC after 1 or 2 prior lines of systemic therapy including S. Overall, median OS was 10.2 mo for C vs 8.0 mo for P (HR 0.76, 95% CI 0.63–0.92; p = 0.0049), and median PFS was 5.2 mo for C vs 1.9 mo for P (HR 0.44, 95% CI 0.36–0.52; p < 0.0001). Here, outcomes were analyzed for pts who had received S as the only prior systemic therapy. Methods: In the overall study, 707 pts were randomized 2:1 to receive C (60 mg qd) or P stratified by disease etiology, geographic region, and extent of disease. Eligible pts had pathologic diagnosis of HCC, Child-Pugh score A, and ECOG PS ≤1. Pts must have received prior S and could have received up to two lines of prior systemic therapy for HCC. Outcomes were analyzed for pts who received only prior S based on duration of prior S ( < 3 mo, 3 to < 6 mo, and ≥6 mo). Results: Out of the 495 pts who received only prior S, 136 (27%) received prior S for < 3 mo, 141 (28%) for 3 to < 6 mo, and 217 (44%) for ≥6 mo. OS and PFS were improved for C vs P in pts who had received only prior S; median OS was 11.3 mo for C vs 7.2 mo for P (HR 0.70), and median PFS was 5.5 mo for C vs 1.9 mo for P (HR 0.40). Results for OS and PFS also favored C for subgroups based on duration of prior S (Table). Median OS was generally longer for pts who received prior S for longer durations in both treatment arms. Grade 3/4 adverse events in subgroups were similar to those observed in the overall population in both arms. Conclusions: C improved OS and PFS vs P in pts with advanced HCC who had received S as the only prior systemic therapy irrespective of the duration of prior S treatment. Clinical trial information: NCT01908426. Prior S Only Duration of Prior S < 3 mo 3 to < 6 mo ≥6 mo C (N = 331) P (N = 164) C (N = 89) P (N = 47) C (N = 98) P (N = 43) C (N = 143) P (N = 74) Median OS, mo 11.3 7.2 8.9 6.9 11.5 6.5 12.3 9.2 OS HR (95% CI) 0.70 (0.55–0.88)* 0.72 (0.47–1.10) 0.65 (0.43–1.00) 0.82 (0.58–1.16) Median PFS, mo 5.5 1.9 3.8 1.8 5.4 1.9 5.7 1.9 PFS HR (95% CI) 0.40 (0.32–0.50)* 0.35 (0.23–0.52) 0.37 (0.25–0.56) 0.48 (0.35–0.67) *Stratified; all other HRs are unstratified.
TCT-839 Transcatheter Aortic Valve Replacement for Severe Aortic Stenosis is More Likely to Improve than Worsen CKD Stage: Analysis of the PARTNER 1, 2A, and S3 Trials
Authors: Roberto J. Cubeddu, Craig Asher, Ashley Lowry, Eugene H. Blackstone, Samir Kapadia, Nirat Beohar, Vinod Thourani, Michael Mack, Susheel Kodali, Howard Herrmann, Jessica Forcillo, Vasilis Babaliaros, Chandan Devireddy, S. Malaisrie, Charles Davidson, Wael Jaber, Martin Leon, Lars Svensson
Journal: Journal of the American College of Cardiology (2018)