tbuckley/cabot-search huggingface dataset:
Frequencies and expression levels of programmed death ligand 1 (PD-L1) in circulating tumor RNA (ctRNA) in various cancer types.
Authors: Toshiyuki Ishiba, Joshua L. Usher, Yahya Elshimali, Sadanand Vodala, Todd Sturdevant, Mai Dang, Mary Grino, Ronald Gonzalez, Yolanda S Jaimes, Rama Tyagi, Jacek K. Pinski, Afsaneh Barzi, Luis E. Raez, Andreas Claudius Hoffmann, Heinz-Josef Lenz, Hiroyuki Uetake, Peter V. Danenberg, Kathleen Danenberg
Journal: Journal of Clinical Oncology (2016)

e23101 Background: Precision medicine and prediction of therapeutic response requires monitoring potential biomarkers before and after treatment. Liquid biopsies provide noninvasive prognostic markers such as circulating tumor DNA and RNA. Circulating tumor RNA (ctRNA) in blood is also used to identify mutations in genes of interest, but additionally, provides information about relative expression levels of important genes. In this study, we analyzed PD-L1 expression in ctRNA isolated from various cancer types. Tumors inhibit antitumor response by modulating the immune checkpoint proteins programmed death ligand 1 (PD-L1) and its cognate receptor PD1. The expression of these genes has been implicated in evasion of immune response and resistance to targeted therapies. Methods: Blood samples were collected from gastric (GC), colorectal (CRC), lung (NSCLC), breast (BC), prostate cancer (PC) patients, and a healthy control group. ctRNA was purified from fractionated plasma, and following reverse transcription, levels of PD-L1 expression were analyzed using qPCR. Results: PD-L1 expression was detected in the ctRNA of 33.3% (3/9 plasma samples) of GC patients, 23.4% (22/94) of CRC patients, 39% (16/41) of NSCLC patients, 54.5% (6/11) of BC patients and 35.3% (6/17) of PC patients. PD-L1 mRNA was not detected in the cancer-free group (0/9), but this was not significantly different from the cumulative cancer patients (p = 0.0602, Fisher’s Exact Test). The frequency of PD-L1 expression was significantly different among the cancer types we studied (p< 0.0001, Fisher’s Exact). However, median relative PD-L1 expression was not statistically significantly different (7.0 in GC, 5.6 in CRC, 10 in NSCLC, 7.8 in BC, and 9.1 in PC) (p = 0.258, Median Test). Conclusions: PD-L1 mRNA can be detected and quantitated in ctRNA of cancer patients. The frequency of PD-L1 expression varies by cancer type, however, when detected in ctRNA, levels of PD-L1 expression do not significantly differ across these cancers. These results pave the way for further studies aimed at determining whether monitoring the levels of PD-L1 mRNA in blood can identify patients who are most likely to benefit from the conventional treatment.
Frequency of PDL-1 expressed on circulating epithelial tumor cells (CETCs) compared to PDL-2 and role in immune evasion in cancer progression.
Authors: Monika Pizon, Dorothea Schott, Ulrich Pachamnn, Katharina Pachmann
Journal: Journal of Clinical Oncology (2016)

3071 Background: The current cancer research strongly focuses on the immune therapies, where the programmed death-1 receptor (PD-1), with its ligands PD-L1 and PD-L2 play an important role. It is known that PDL-1 is frequently upregulated in a number of different cancers and the relevance of this pathway has been extensively studied and therapeutic approaches targeting PD-1 and PD-L1 have been developed. However, PD-L2 has not received as much attention and its role in modulating tumor immunity is less clear. To identify potential patients who may benefit from PD-1/PD-L1/PD-L2 targeted immunotherapeutics, we used a non-invasive, real-time liquid biopsy for determining PD-L1 and PDL-2 expression in CETCs of breast cancer patients. Methods: CETCs were determined from blood of 66 patients suffering from breast cancer. The number of vital CETCs and the expression of PDL-1 and PDL-2 were investigated using the maintrac method. Results: PDL-1 expressing CETCs were detected in 95 % of breast cancer patients whereas only 75% patients had PDL-2 positive CETCs. There was no association between the frequency of PDL-1 positive CETCs and progression of cancer disease. We found that the fraction of PDL-1 positive CETCs is significantly higher than the fraction of PDL-2 positive CETCs (63.3% vs. 32.9%; p ). Moreover, we observed a significant heterogeneity in PDL-1 and PDL-2 immunostaining intensity across CETCs from the same patients. Conclusions: Breast cancer patients have detectable CETCs with high frequency of PDL-1 regardless of stage of disease. PDL-1 seems to be a major factor in immune evasion and may be a promising target of anticancer therapies. Monitoring the frequency of PDL-1 positive CETCs could reflect individual patient’s response for an anti-PD-1/PDL-1 therapy.
Definitive concurrent chemoradiotherapy (CRT) for locally advanced squamous cell carcinoma of the head and neck (LA-SCCHN) using systemic dose carboplatin: A retrospective analysis.
Authors: Misako Nagasaka, Mark A. Zaki, Majd Issa, Harold E. Kim, Judith Abrams, Ammar Sukari
Journal: Journal of Clinical Oncology (2016)

e17538 Background: Definitive concurrent CRT is considered the standard of care for organ preservation and is the only potentially curative therapy in surgically unresectable patients (pts) with stage III-IVb, LA-SCCHN. The standard regimen is 70 Gy (2 Gy/fraction) over 7 weeks with concurrent cisplatin 100 mg/m2 on days 1, 22, and 43. This was established by trials utilizing cisplatin-based CRT. In pts considered to have high risks for adverse events (AEs) with cisplatin, carboplatin has been empirically substituted as an alternative regimen. However, limited data are available regarding the outcomes of pts treated with carboplatin-based CRT. Methods: Data from pts with LA-SCCHN who underwent CRT with carboplatin at our institution in the years 2007-2013 were reviewed. The primary objective was to estimate local-regional control (LRC) rate. Secondary objectives were estimation of progression free survival (PFS), overall survival (OS) as well as laryngectomy rates in LC pts. AEs were assessed according to CTCAE v4. Results: 54 pts with LA-SCCHN who underwent definitive CRT with carboplatin (AUC of 5) were included. Median age was 60.5 (range: 38-80). 42 (78%) were male. 13 (24%) had CKD ≥stage 3. There were 4 (7%) non-resectable oral cavity (OCC), 19 (35%) oropharyngeal (OPC), 3 (6%) hypopharyngeal (HPC), 27 (50%) laryngeal (LC) and 1 (2%) with unknown primary SCCHN. Overall LRC rate was 50% (95% CI 37-63%). The laryngectomy rate in LC pts was 41% (CI 25-59%). Median PFS and OS were 21 (CI 11-33) and 40 (CI 33-NA) months, respectively. 1, 3 and 5 year OS were 81% (CI 67-89%), 59% (CI 41-73%) and 42% (CI 22-61%), respectively. Stage III/IVa pts (n = 45) had a median OS of 62 (CI 37-NA) months and 3 year OS of 71% (CI 53-84%) whereas stage IVb (n = 9) had a median OS of 31 (CI 4-NA) months and none survived to 3 years. Dysphagia was the most common AE; 21 pts with grade 2 (39%) and 20 with grade 3 (37%). Myelosuppression was also common; with ≥grade 3 anemia, neutropenia, and thrombocytopenia seen in 17%, 13%, and 15%, respectively. Conclusions: Definitive CRT with carboplatin for LA-SCCHN was well tolerated and demonstrated comparable results to CRT with cisplatin.
SM-88 in advanced cancers of the pancreas (SMACP).
Authors: Marcus Smith Noel, Allyson J. Ocean, Gerald H. Sokol, Steve Hoffman, Giuseppe Del Priore
Journal: Journal of Clinical Oncology (2018)

TPS4156 Background: Treatment options for recurrent/refractory advanced pancreatic cancer (PC) include largely ineffective toxic therapies or palliation. SM-88 is a combination of dysfunctional tyrosine derivative (TD), mTOR inhibitor, CYP3a4 inducer and oxidative stress catalyst, previously reported to have activity in a variety of cancers and settings, with no drug-related grade 3 or 4 toxicity (J Clin Oncol 36, 2018 (suppl 6S; abstr 175. JCO 35, 2017 (supp e14060) Reduction of circulating tumor cells (CTCs), RECIST responses and prolonged duration of clinical benefit have also been reported with SM-88 in multiple tumor types including PC. (J Clin Oncol 31, 2013 (suppl; abstr e22095). We now describe an ongoing trial of SM-88 in metastatic PC. Methods: This is a prospective, multicenter ( > 30 sites), North American Phase II trial evaluating SM-88 as a single agent in recurrent PC. Eligible patients must have histologically confirmed metastatic PC, ECOG PS < 3, measurable disease, and have received at least one line of prior therapy. MSI-H tumors must have had targeted therapy. 36 subjects are planned for the 1st stage, randomized 1:1 between the currently utilized clinically active regimen and a 2X dose, with the expansion dose selected based on clinical benefit and toxicity. Using Fleming’s two-stage minimax design, based on overall response rate at 16 weeks, with H(0): ORR < 8% vs H(1): ORR > 16% ,99 evaluable will be required, yielding > 95% power to detect an OS of 90% at 6 months compared to historical OS of 55%. Primary endpoints are ORR and OS. Secondary endpoints include PFS ratio, disease control rate duration of response, and time to subsequent treatment. Correlative studies include circulating tumor cells (CTCs) with genomics, tumor markers, EORTC QLQ-C30 and EORTC QLQ-PAN26, pharmacokinetics, pro-insulin, leptin and neutrophil:lymphocyte ratio, A known toxicity of SM-88 is skin hyperpigmentation and this will be investigated as a possible biomarker along with other exploratory endpoints. Clinical trial information: NCT pending
PK/PD properties of BI 836880, a vascular endothelial growth factor (VEGF)/angiopoietin-2 (Ang-2)-blocking nanobody, in patients (pts) with advanced/metastatic solid tumors.
Authors: Christophe Le Tourneau, Josep Tabernero, Rainer Claus, Ralph M Fritsch, Francesco Ricci, Elena Elez, Björn Hackanson, Ulrich Kunz, Thomas Arnhold, Heiko Niessen, Sascha Keller, Ralph Graeser, Nicolas Isambert
Journal: Journal of Clinical Oncology (2018)

2523 Background: BI 836880 (q3w or qw, iv) was evaluated in two first-in-human, Phase I trials in pts with advanced/metastatic solid tumors. We report exploratory PK/PD analysis of these studies to support dose selection for further clinical development of BI 836880. Methods: PK/PD analysis used evaluable data from 23 pts treated over ≥1 cycle (14 q3w; 9 qw [pt accrual ongoing in the qw schedule to confirm the maximum tolerated dose]). Analytes were systemic BI 836880, free VEGF, free Ang-2 and total Ang-2. Levels of BI 836880 in plasma were analyzed using a LC-MS/MS method, via monitoring a unique peptide of BI 836880 (lower limit of quantification [LLOQ] 0.5 mg/L). Total and free systemic Ang-2 were analyzed using ELISAs (LLOQ 0.1 and 0.08 ng equivalents [ngeq]/mL). Free systemic VEGF was analyzed using ECLIA with LLOQ 2.7 pgeq/mL. Development of an assay for total VEGF is ongoing. DCE-MRI data, as PD markers, were evaluated in 8 pts. Results: BI 836880 plasma kinetics appeared dose-proportional over 40–1000 mg q3w and 40–180 mg qw, with accumulation ratios between 1 and 2.The geometric mean half-life of BI 836880 in the q3w schedule over all dose groups was 8.2 days (cycle 1; n = 12), 9.9 days (cycle 2; n = 7) and 14.3 days (cycle 4; n = 4). Required trough values (20 mg/L; predicted based on preclinical experiments) were achieved at doses ≥720 mg q3w.Predose free VEGF levels were 0.022 to 0.669 ngeq/mL. Predose free Ang-2 levels were 0.72 to > 15 ngeq/mL. Individual pt PK/PD profiles showed that free VEGF was below LLOQ at the lowest dose; free Ang-2 was blocked dose-dependently and was below LLOQ at doses ≥360 mg q3w or 120 mg qw. Both analytes remained below LLOQ at these doses even before the next treatment cycle. Total Ang-2 (the majority bound to BI 836880) increased 100- to 1000-fold above predose levels and for some samples to the upper LOQ (1000 ngeq/mL). Ktrans (capillary permeability) decreases ≥20% were observed in 5/7 pts at the 720 mg q3w dose, including 3 with Ktrans reduction > 40%. Conclusions: PK/PD analysis supported BI 836880 720 mg q3w as the biologically relevant dose. DCE-MRI analysis confirmed anti-angiogenic activity in the tumor at this dose. Clinical trial information: NCT02674152; NCT02689505.
TCT-123 Impact of Delirium on TAVR Outcomes
Authors: Brett Hiendlmayr, Jeff Mather, Lauren Curtis, Kerry McGuire, None nichole hoover, Mohiuddin Cheema, None david underhill, William Duvall, Robert Hagberg, Jennifer Jantz, sean McMahon, Talhat Azemi, Immad Sadiq, Francis Kiernan, Raymond McKay
Journal: Journal of the American College of Cardiology (2018)
Circulating tumor DNA to predict timing of relapse in mantle cell lymphoma.
Authors: Mark J. Roschewski, Christopher Joseph Melani, Stefania Pittaluga, Kieron Dunleavy, Nakhle S. Saba, Cliona Grant, Joan Aaron, Allison Jacob, Erik Yusko, Seth M. Steinberg, Elaine S. Jaffe, Adrian Wiestner, Wyndham Hopkins Wilson
Journal: Journal of Clinical Oncology (2018)

7576 Background: Mantle cell lymphoma is clinically heterogeneous. MRD- after frontline therapy improves PFS, but virtually all pts relapse. Surveillance after induction is not uniform and clinical decisions are empirical. Detection of ctDNA in the blood throughout therapy is promising. We used AdaptiveÕs next-generation sequencing assay to detect and quantify ctDNA in blood throughout therapy for MCL. Methods: Untreated MCL pts received bortezomib (BZ) + DA-EPOCH-R x 6 then randomized to obs vs. BZ maint x 18m. Pt serum collected pre-Tx, w/each cycle, and w/each surveillance visit paired w/CT scans at regular intervals for 5y. FFPE was analyzed for tumor-specific clonotypes. Tumor DNA was amplified using locus-specific primer sets for the Ig heavy-chain and light-chain loci, BCL1, and BCL2 translocations. Amplified products were sequenced, and pts w/o a high-frequency tumor clonotype excluded. Baseline ctDNA levels were compared to tumor burden and proliferation. Levels of ctDNA at EOI and during surveillance were analyzed for the ability to predict progression. Results: 53 MCL pts were treated between 1996 and 2013. After median f/u of 9.6y, 5-yr OS is 80.1% and median PFS is 30.7m. With FFPE available, 50 of 52 (96%) had an tumor-specific clonotype, and 46 of 48 pts (96%) had detectable ctDNA in serum prior to therapy. ctDNA was successfully tracked in 625 of 647 (97%) serum samples. Pre-treatment ctDNA levels more strongly correlated with total metabolic tumor volume (rs= 0.74) than Ki-67 (rs= 0.55) or serum LDH (rs= 0.49). Overall, 47 pts responded to induction (44 CR; 3PR), and median TTP after EOI was 26m (range 0-131). 40 of 50 pts (80%) achieved MRD- at EOI, which was assoc with superior median PFS (45m vs. 25m, p = 0.001) and OS (NR vs. 40m, p = 0.01) vs. MRD+ pts. In 31 of 41 (76%) progressors, ctDNA was present prior to clinical progression with a median lead-time of 9m (range 0-38). Of 9 non-progressors, 8 remained ctDNA negative. BZ maint had no impact on PFS or OS. Conclusions: Nearly all pts with MCL have detectable baseline ctDNA. Achieving MRD- at EOI was associated with improved PFS and OS compared to MRD+ pts. ctDNA was detected a median 9m before progression. Clinical trial information: NCT00114738.
Prognostic impact of <i>COL5A2</i> and <i>ACVR1B</i> genes in intestinal high risk localized GIST. A Spanish Group for Research on Sarcoma (GEIS) study.
Authors: Javier Martin Broto, Antonio Fernandez-Serra, Antonio Gutierrez, Irene Felipe, Jose Duran, Silvia Calabuig-Fariñas, Dolors Sanchez-Izquierdo, Nadia Hindi, Andres Poveda, Regina Alemany, Jose Antonio Lopez-Guerrero
Journal: Journal of Clinical Oncology (2016)

e22514 Background: Molecular prognostic factors related to recurrence in localized GIST are still scarce so that this recurrence risk relies on clinical and pathologic factors as mitotic count, size, location and capsule rupture. Our group has previously reported the prognostic relevance for relapse free survival (RFS) of let-7e microRNA in 89 high risk intestinal localized GIST. The median of RFS were 26 (19.5-32.6) vs 50 (24.6-39.7) months for below and above median values of let-7e respectively (p = 0.011). The next step in the research was to identify those let-7e target genes that could play a prognostic role for recurrence in this specific GIST population Methods: A screening of putative let-7e targets with a series of 10 FFPE GIST samples, 4 with relapse and 6 corresponding to no relapse was performed first. Samples using a RT2 Profiler PCR Array of human let-7 (Qiagen) which determines the expression of 84 genes described biological or bionformatically as interesting targets of this miRNA were analysed. This technique is based in a two steps Real Time PCR. Afterwards, gene expression of selected genes was analysed in the large validation series and genes were dichotomized using median value as cut-off. Kaplan–Meier estimations were used for time-to-event variables and the log-rank test was used to compare groups. Relapse free survival was the clinical endpoint Results: The four most upregulated genes found were: CASP3 (Fold Change = 6.93, p = 0.0029), COL5A2 (FC = 5.97 p = 0.015), ACVR1B (FC = 4.97 p = 0.049) and COL3A1 (FC = 4.44 p = 0.039) with a series of 10 FFPE GIST samples. The analysis of these four genes in 64 localized high risk intestinal localized GIST cases (41 relapsed and 23 no relapsed) showed a significant worse RFS if both genes, COL5A2 and ACVR1B, were overexpressed: 26.1 (13.8-38.3) months vs 42.7 (19.3-66.1) months for overexpression of both genes or not respectively, p = 0.031. Conclusions: Overexpression of COL5A2 and ACVR1B have shown to be bad prognostic factors in the context of high risk intestinal localized GIST. Currently we are expanding the analyses in the validation set.
Abstract 13518: Low Skeletal Muscle Mass Index is Associated With Cardiovascular Events in Patients After ST-segment Elevation Myocardial Infarction
Authors: Ryosuke Satou, Yasushi Matsuzawa, Eiichi Akiyama, Hiroyuki Suzuki, Chika Kawashima, Masaaki Konishi, Yuuichiro Kimura, Katsutaka Hashiba, Nobuhiko Maejima, Noriaki Iwahashi, Kiyoshi Hibi, Masami Kosuge, Toshiaki Ebina, Shinichi Sumita, Kazuo Kimura
Journal: Circulation (2016)

Introduction: Although it has been implicated the association between low skeletal muscle mass and cardiovascular diseases, the prognostic value of skeletal muscle mass in patients with ST-segment elevation myocardial infarction (STEMI) is unclear. Hypothesis: We assessed the hypothesis that low skeletal muscle mass index (SMMI) is associated with an increased risk of secondary cardiovascular events in patients with STEMI. Methods: A total of 200 patients with STEMI were enrolled. SMMI was estimated from dual-energy X-ray absorptiometry scan before discharge, and calculated by dividing appendicular skeletal muscle mass (kg) by height squared (m 2 ). The patients were divided into low and high SMMI groups using the first tertile of SMMI. Low SMMI was defined as ≤6.843 kg/m 2 for men and ≤5.321 kg/m 2 for women. All patients were followed for cardiovascular events, which consist of cardiovascular deaths, nonfatal myocardial infarctions, nonfatal ischemic strokes, and congestive heart failure. Results: During follow-up (median 340 days [interquartile ranges 298 and 389]), 15 patients experienced cardiovascular events (1 cardiovascular death, 6 myocardial infarction, 6 stroke, and 3 congestive heart failure). The event rate at 1 year after STEMI was significantly higher in patients with low SMMI (15.5%) than with high SMMI (2.5%) (log-rank p&lt;0.001) (Figure). Even after adjustment for the propensity score which was calculated with age, gender, height, weight, risk factors and medications, patients with low SMMI had 5.8-fold higher risk of subsequent cardiovascular events compared to those without (Adjusted hazard ratio 5.86, 95% confidence interval 1.18 to 35.28, p=0.03). Conclusion: Among patients with STEMI, low SMMI was significantly and independently associated with an increased risk of future cardiovascular events.
Circulating cell-free DNA: The future of personalized medicine in ovarian cancer management.
Authors: Rebecca Christian Arend, Angelina I Londono, Ronald David Alvarez, Warner King Huh, Kerri S. Bevis, Charles A. Leath, John Michael Straughn
Journal: Journal of Clinical Oncology (2016)

5577 Background: The objective of this study is to evaluate the utility of circulating cell-free DNA (cfDNA) in plasma to molecularly profile patients with ovarian high-grade serous carcinoma (HGSC). Methods: Under IRB approval, we collected plasma and tumor from 14 patients with advanced HGSC before and after treatment with neoadjuvant chemotherapy (NACT). Plasma cfDNA and tumor DNA from each patient were subjected to next generation sequencing utilizing a 50-gene mutation panel. Mutations in cfDNA and tumor DNA specimens, both prior to and after NACT, were compared. Results: Plasma cfDNA appears to detect more targetable mutations. Specifically, the cfDNA prior to NACT contained 19 mutated genes with 57 specific mutations; the tumor contained 6 mutated genes with 38 specific mutations (Table). Five of the 19 genes noted to be mutated in the cfDNA prior to NACT have FDA-approved targeted agents and 7 patients could have been candidates for these drugs, compared to only one targetable mutated gene in the tumor. Similar findings were noted with respect to mutations in the cfDNA when compared to the tumor DNA after NACT. Specifically, 21 mutated genes with 54 mutations were identified in the cfDNA compared to 6 mutated genes and 37 mutations in the tumor. Seven of the 21 genes noted to be mutated in the cfDNA post NACT had targeted agents, and 8 patients could have been candidates for these drugs, while only one targetable mutated gene in the tumor. Over the course of NACT, cfDNA showed more change in the genetic diversity. Specifically, of the 57 mutations in the plasma pre NACT, only 6 persisted after treatment, whereas 33 of 38 mutations in the tumor were the same after NACT. Conclusions: Plasma cfDNA detects more mutations than DNA extracted from solid tumor and may better capture clonal evolution of genetic alterations. Precision medicine programs should consider utilizing cfDNA to optimize detection of the molecular diversity of ovarian cancer when performing genetic profiling. cfDNA (plasma) DNA (tumor) Pre Post Pre Post # mutatedgenes 19 21 6 6 # mutations 57 54 38 37 Most frequentlymutated P53 (20) P53 (17) P53 (23) P53 (23) PI3KCA (6) KIT (7) KDR (5) KDR (6) KIT (5) PI3KCA (5) KIT (5) KIT (4) EGFR (4) CTNNB1 (3) PIK3CA (3) PIK3CA (2)