tbuckley/cabot-search huggingface dataset:
A Real-time PCR Assay for the Detection of EGFR Mutations in FFPE Tissue and Plasma Samples of NSCLC Patients.
Authors: Patrick O'Donnell, Johnny Shyu, Jane Ferguson, Kelli Demartin, Theresa May, Deborah Jensen, Mandana Celeri, Taraneh Rehage, Lilia Corona, Robert Current, Snehal Joshi, Yiqiao Wu, Muskan Floren, Stephen Soviero
Journal: Journal of Clinical Oncology (2016)

e23251 Background: The cobas EGFR Mutation Test v2 (cobas EGFR test) is a real-time PCR test for the qualitative detection of 42 mutations in exons 18, 19, 20, and 21 of the epidermal growth factor receptor (EGFR) gene in DNA derived from formalin-fixed paraffin-embedded (FFPET) tumor tissue and human plasma from non-small cell lung cancer (NSCLC) patients. The test is also indicated for the semi-quantitative measurement of these EGFR mutations in plasma, allowing for serial measurements as an aid in management of NSCLC patients. Methods: The assay’s limit of detection (LoD) was determined using 31 FFPET derived DNA blends and 27 contrived, healthy donor plasma sample blends with intact (21) or sheared (6) cell line DNA. Assay performance for 118 FFPET and 74 plasma NSCLC specimens was compared between the cobas EGFR test and Next Generation Sequencing (NGS). The FFPET specimens were also compared with v1 and v2 of the cobas EGFR test. Internal repeatability was assessed in duplicate with different operators, reagent lots, and instruments across multiple days using FFPET specimens and contrived healthy donor plasma samples with intact cell line DNA. Linearity was established testing contrived healthy donor plasma sample blends with intact cell line DNA. Results: FFPET: LoD for detecting EGFR mutations of FFPET samples is ≤ 5% mutation level using the standard input of 50 ng per reaction well. The cobas EGFR test v2, when compared to the original test (v1), had positive (PPA), negative (NPA), and overall (OPA) percent agreement of 95%, 100%, and 97% respectively. The cobas EGFR test v2, when compared to NGS, had PPA of 87%, NPA of 100%, and OPA of 93%. Two internal repeatability studies had call accuracies of 96.3% and 99.2%. Plasma: LoD for detecting EGFR mutations in plasma samples is ≤ 100 cp/mL. The cobas EGFR test v2, when compared to NGS had PPA of 80.0%, NPA of 94.9%, and OPA of 87.8%. An internal repeatability study had a call accuracy of 99.1%. The cobas EGFR test v2 with plasma samples is linear between 100 and 10,000 cp/mL. Conclusions: The cobas EGFR Mutation Test v2 is a sensitive, accurate, rapid, and reproducible assay capable of testing DNA isolated from either FFPET or plasma from NSCLC patients.
TREM-1 expression in HPV related oropharyngeal squamous cell carcinoma (OP-SCC).
Authors: Mario Airoldi, Luca Raimondo, Barbara Azzimonti, Diletta Francesca Squarzanti, Luigi Chiusa, Mauro Papotti, Paola Cappello, Giancarlo Pecorari, Guido Valente
Journal: Journal of Clinical Oncology (2018)

e18037 Background: to evaluate the lymphocyte population, PD-1, PDL-1 and TREM-1 expression to better understand the immunophenotype of HPV+ OP-SCC Methods: 30 specimens of advanced stage OP-SCC resected between 2004 and 2012; exclusion criteria: bony invasion, recurrent/metastatic disease, previous RT/CT for HNSCC, previous CT for other site solid and/or hematological tumors and immunosuppressive therapy. IHC for p16 and E6, CD4, CD8, PD-1, PDL-1 and TREM-1 was performed on consecutive sections. Here we report data about first 17 cases. Results: p16 was positive in 60% of pts(24%+;36%++); E6 was positive in 100% of pts(59%+;41%++); ITE: CD4 was positive in 100% of pts(12%+;24%++;64%+++) as CD8(12%+;36%++;53%+++), PD-1 was negative in 29% and positive in 71% of pts(71%+), PDL-1 on tumoral cells was positive in 100% of pts(53%+;48%++), TREM-1 was negative in 82% and positive in 18%(12%+;6%++); PTE: CD4 was positive in 100% of pts(6%+;24%++;71%+++) as CD8(48%+; 41%++; 12%+++), PD-1 expression was negative in 59% and positive in 41% of pts(41%+), PDL-1 expression was positive in 100% of pts(6% +;59%++;36%+++) TREM-1 was negative in 18% and positive in 82%(64%+;18%++). McNemar test showed a concordant expression of CD4, CD8, and PDL-1 both in ITE and PTE, while TREM-1 was more expressed in PTE(p = 0.001) and PD-1 in ITE(p = 0.12) Conclusions: For the first time, we described a high expression of TREM-1 in the PTE and this finding could have a clinical relevance because TREM-1 triggering reverses the M2-polarizing effect of hypoxia imparting a M1-skewed proinflammatory phenotype to macrophages that controls tumor growth.
TCT-375 Current Generation Balloon-Expandable Transcatheter Valve Positioning During Aortic Valve-in-Valve Procedures and Clinical Outcomes
Authors: Matheus Simonato, John Webb, Moritz Seiffert, Sabine Bleiziffer, Ulrich Schäfer, Jochen Wöhrle, David Jochheim, Felix Woitek, Azeem Latib, Marco Barbanti, Konstantinos Spargias, Susheel Kodali, Tara Jones, Didier Tchetche, Mohamed Abdel-Wahab, Rafael Coutinho, Massimo Napodano, Santiago Garcia, Tobias Zeus, Dimytri Siqueira, Stephan Windecker, Alfredo Cerillo, Nikolaos Bonaros, Wolfgang Schoels, Hardy Baumbach, Joachim Schofer, Danny Dvir
Journal: Journal of the American College of Cardiology (2018)
Targeted MCL-1 inhibition to induce cell death and synergize with conventional chemotherapeutic agents in diffuse large B-cell lymphoma (DLBCL) pre-clinical models.
Authors: Robert Zachary Ferdman, Jenny Gu, Cory Mavis, Pallawi Torka, Francisco J. Hernandez-Ilizaliturri
Journal: Journal of Clinical Oncology (2018)

e14540 Background: Bcl-2 inhibition has been explored therapeutically in B-cell malignancies. Venetoclax’s activity, a novel Bcl-2 inhibitor, is limited in Mcl-1 over-expressing DLBCL. The MCL-1, an anti-apoptotic Bcl-2 family member, has been implicated in chemotherapy resistance in DLBCL. MCL-1 silencing in DLBCL cell lines is lethal. We hypothesize that Mcl-1 inhibition with AMG-176, a novel Mcl-1 inhibitor, may result in significant anti-tumor activity in DLBCL. Materials and Methods: A panel of DLBCL cell lines including 7 germinal center B-cell, 4 activated B-cell and 3 double-hit were tested, including two rituximab-chemotherapy resistant cell lines generated in our laboratory. Cells were exposed to escalating doses of AMG-176 (0-20uM) for 24, 48 and 72 hrs. IC50 were calculated for each cell lines. Subsequently, DLBCL cells were exposed to AMG-716 alone and in combination with doxorubicin (0-1µM), cisplatin (0-100µM) and cytarabine (0-100µM) for 72 hrs. Changes in cell viability were measured changes in ATP content. Coefficient of synergy was calculated using CalcuSyn software. In addition, baseline levels of Mcl-1 and other key members of the Bcl-2 family of proteins was evaluated by Western Blotting. Results: In Vitro exposure of DLBCL cell lines to AMG-176 as a single agent induced cell death in a dose-dependent manner. Activity was observed in all types of cell lines tested. AMG-716 IC50 values ranged between 0.003 to 15.9 µM. Synergistic activity was observed between AMG-176 and all chemotherapy agents tested. Mcl-1 expression appeared to correlate with AMG-17 sensitivity. Conclusions: Our data suggests that AMG-176 exhibits significant anti-tumor activity against a variety of DLBCL cell lines representing different subtypes of DLBCL. Synergistic activity was observed between AMG-716 and chemotherapy. Targeted MCL-1 inhibition combined with standard chemotherapy may provide new therapeutic option for relapsed/refractory DLBCL.
Effects of derivative vitamin D3 in colorectal cancer.
Authors: Teruo Sasatomi, Uhi Toh, Yutaka Ogata, Yoshito Akagi
Journal: Journal of Clinical Oncology (2016)

e15150 Background: Serum activated Vitamin D (Vitamin D3) have been reported to induce differentiation and to be associated with prognosis in colorectal cancer, breast cancer and another carcinomas. Therefore, we investigated the reaction for the colorectal cancer cell lines of Vitamin D and examined possibility of clinic application. Methods: Colorectal cancer cell limes. We employed three colorectal cell lines, HT29 (KRAS wild / BRAF V600K) HCT116 (KRAS 13 mutant / BRAF V600K), SW620 (KRAS 12 mutant / BRAF wild)Vitamin D derivate O2C3 was kindly permitted to use by Teikyo University Dept of Pharmacology. Effect of Vitamin D3 and Vitamin D derivate O2C3 was measuered by MTS Cell Proliferation Assay. (490nm) MDSC (myeloid derived suppressor cells) Assay. PBMC of in post operative recurrence colorectal cancer patient was harvested and measured by FACscan with fluorescence-labeled antibody of CD14, CD11b and CD33. Serum Ca++ levels ware mesured in Balb/C mice injected with Vitamin D3 and Vitamin D derivate O2C3. (5 times, 5mice each) Tumor Depression Colorectal cancer cell lines were injected to nude mouse and thier tumor of weight were mesured. Results: 1. In MTS Cell Proliferation Assay(490nm), both Vitamin D3 and Vitamin D derivate O2C3 showed depression effect for colorectal cancer cell lines, HCT116, SW620 from 72Hrs to 96Hrs. 2. Serum Ca++ levels were depressed within normal limits with Balb/C mouse. Vitamin D derivate O2C3 may be more possible of clinical application than Vitamin D3, which might cause hypercalcemia. 3. Vitamin D derivate O2C3 induced MDSC in PBMC to decrease and it may improve immune depression of the colorectal cancer bearing patients. 4. Tumors of colorectal cancer cell lines in nude mice were observed no progression in tumor weights with Vitamin D derivate O2C3. (P< 0.005). Conclusions: We suggest the Vitamin D derivate, O2C3 may be developed to a new drug for colorectal cancer with KRAS or BRAF mutation and also it may improve immune depression state of the colorectal cancer bearing patients.
EORTC-1203: Integration of trastuzumab (T), with or without pertuzumab (P), into perioperative chemotherapy (CT) of HER-2 positive stomach cancer—INNOVATION trial.
Authors: Anna Dorothea Wagner, Yoon-Koo Kang, Jolanda van Dieren, Murielle E. Mauer, Heike I Grabsch, Michela Lia, Ajlan Atasoy, Jae Yong Cho, Markus H. Moehler, Arnaud Roth, Manuel Salto-Tellez, Christoph Schumacher, Nicole C.T. van Grieken, Johanna W. van Sandick, Florian Lordick
Journal: Journal of Clinical Oncology (2016)

TPS4133 Background: Approximately 10-20% of patients with gastric cancer (GCa) have HER-2 positive tumors. The addition of T to cisplatin/fluoropyrimidine-based CT improved survival in metastatic HER-2 positive GCa. When P was added to T and CT, a significant increase in the histopathological complete response rate was observed in HER-2 positive breast cancer. This study aims to investigate the added value of combining both HER-2 targeting drugs with perioperative CT for GCa and gastroesophageal-junction cancer (GEJCa). Methods: This is a randomized, open-label phase II trial. Biopsies from patients with resectable GCa or GEJCa (UICC tumor stage Ib-III) will be centrally screened for HER-2. Over a 4-year accrual period, 225 patients with HER-2 positive cancers will be centrally randomized (1:2:2 ratio) across 52 centers in 10 European and 3 non-European countries in one of the three arms: - Control arm: Cisplatin (80 mg/m2 every 3 weeks) and capecitabine (1000 mg/m2 twice daily every 2 out of 3 weeks), or 5-FU (800 mg/m2/day for 5 days every 3 weeks) for 3 cycles before and after surgery - Experimental arm 1: CT plus T (8 mg/kg loading dose, followed by 6mg/kg every 3 weeks) - Experimental arm 2: CT plus T plus P (840mg every 3 weeks) T and/or P will be administered on day 1 of every CT cycle and continued afterwards for a total of 17 cycles. Stratification will be done by histological subtype (intestinal/non-intestinal); region (Korea vs Europe); location (GEJCa vs non-GEJCa) and HER-2 (immunohistochemistry 3+ vs IHC 2+/FISH+). The primary objective is to detect an increase in the pathological response rate (RR, < 10% residual tumor cells) as determined by central review, from 15% to 30% with addition of T or T and P. The RR in each experimental arm will be tested versus 15% with a one-sided type I error of 5%. If both tests are positive, the experimental arm with the higher RR will be recommended if the difference exceeds 5%. The recruitment has started in September 2015. Clinical trial information: NCT02205047.
Detection and clearance of <i>RET</i> variants in plasma cell free DNA (cfDNA) from patients (pts) treated with LOXO-292.
Authors: Geoffrey R. Oxnard, Alexander E. Drilon, Manisha H. Shah, Lori J. Wirth, Todd Michael Bauer, Vamsidhar Velcheti, Nehal J. Lakhani, Benjamin Besse, Keunchil Park, Jyoti D. Patel, Maria E. Cabanillas, Eric Jeffrey Sherman, Kyle Gordon, Steven Smith, Michele Nguyen, Edward Zhu, Stephen M. Rothenberg, Kevin Ebata, Brian Benjamin Tuch, Vivek Subbiah
Journal: Journal of Clinical Oncology (2018)

9048 Background: LOXO-292 is a novel, highly-selective, small molecule RET inhibitor in clinical development for pts with advanced cancers harboring oncogenic RET alterations (e.g. non-small cell lung cancer [NSCLC], medullary thyroid cancer [MTC], papillary thyroid cancer [PTC], and any other cancer). Here we study modulation of RET variant allele frequencies (AF) in plasma cfDNA with LOXO-292 therapy. Methods: LOXO-292 is being studied in an ongoing Phase 1 study in pts with advanced solid tumors, with enrollment enriched for pts with RET alterations (NCT03157128). Blood is collected pretreatment, after 15 days of treatment, and at each restaging for cfDNA analysis by next-generation sequencing (NGS, Guardant). Results: As of 1/5/18, 57 pts were enrolled (35 RET fusion+ (27 NSCLC, 7 PTC, 1 other), 20 RET-mutant MTC, 2 other) to 7 doses (20mg QD→160mg BID). 213 plasma samples were collected. Here we report on 44 pts with plasma NGS results available. Of 41 pts enrolled based on a RET variant detected in a tumor sample, concordant RET alterations were detected in 26 (63%) of the corresponding pre-treatment plasma samples, including 15/22 (68%) pts with RET-fusion NSCLC and 8/12 (67%) pts with RET-mutant MTC. Median AF was higher for MTC (6.9%) than NSCLC (0.7%). In negative pre-treatment samples, peak AF for other detected alterations was low (0.3% median), suggesting low tumor DNA shed into plasma. Of 18 pts with a detectable pre-treatment plasma RET alteration and day 15 plasma NGS, RET alteration AF decreased by a median of 92%, with complete clearance in 7 pts (39%). Day 15 plasma clearance was observed at multiple doses (20-60mg BID), and was more common in RET fusion-positive (55%) than RET-mutant (14%) pts. Data for additional pts will be updated at the time of presentation. Conclusions: The rapid clearance of RET variants from plasma cfDNA on LOXO-292 supports its observed clinical activity across a range of doses, tumor types and RET alterations. NGS of plasma cfDNA can detect a range of targetable RET variants, though tumor genotyping remains critical if the initial plasma NGS is negative. Serial plasma genotyping warrants continued study as an early pharmacodynamic marker for novel targeted therapies. Clinical trial information: NCT03157128.
Cyclin D1-CDK4 activity drives sensitivity to bortezomib in mantle cell lymphoma by blocking autophagy-mediated proteolysis of NOXA
Authors: Simon Heine, Markus Kleih, Neus Giménez, Kathrin Böpple, German Ott, Dolors Colomer, Walter E. Aulitzky, Heiko van der Kuip, Elisabeth Silkenstedt
Journal: Journal of Hematology & Oncology (2018)

Mantle cell lymphoma (MCL) is an aggressive B-non-Hodgkin lymphoma with generally poor outcome. MCL is characterized by an aberrantly high cyclin D1-driven CDK4 activity. New molecular targeted therapies such as inhibitors of the ubiquitin-proteasome system (UPS) have shown promising results in preclinical studies and MCL patients. Our previous research revealed stabilization of the short-lived pro-apoptotic NOXA as a critical determinant for sensitivity to these inhibitors. It is currently unclear how cyclin D1 overexpression and aberrant CDK4 activity affect NOXA stabilization and treatment efficacy of UPS inhibitors in MCL. The effect of cyclin D1-driven CDK4 activity on response of MCL cell lines and primary cells to proteasome inhibitor treatment was investigated using survival assays (Flow cytometry, AnnexinV/PI) and Western blot analysis of NOXA protein. Half-life of NOXA protein was determined by cycloheximide treatment and subsequent Western blot analysis. The role of autophagy was analyzed by LC3-II protein expression and autophagolysosome detection. Furthermore, silencing of autophagy-related genes was performed using siRNA and MCL cells were treated with autophagy inhibitors in combination with proteasome and CDK4 inhibition. In this study, we show that proteasome inhibitor-mediated cell death in MCL depends on cyclin D1-driven CDK4 activity. Inhibition of cyclin D1/CDK4 activity significantly reduced proteasome inhibitor-mediated stabilization of NOXA protein, mainly driven by an autophagy-mediated proteolysis. Bortezomib-induced cell death was significantly potentiated by compounds that interfere with autophagosomal function. Combined treatment with bortezomib and autophagy inhibitors enhanced NOXA stability leading to super-induction of NOXA protein. In addition to established autophagy modulators, we identified the fatty acid synthase inhibitor orlistat to be an efficient autophagy inhibitor when used in combination with bortezomib. Accordingly, this combination synergistically induced apoptosis both in MCL cell lines and in patient samples. Our data demonstrate that CDK4 activity in MCL is critical for NOXA stabilization upon treatment with UPS inhibitors allowing preferential induction of cell death in cyclin D transformed cells. Under UPS blocked conditions, autophagy appears as the critical regulator of NOXA induction. Therefore, inhibitors of autophagy are promising candidates to increase the activity of proteasome inhibitors in MCL.
An open-label, multicenter, phase II single arm trial of osimertinib in non-small cell lung cancer patients with uncommon EGFR mutation (KCSG-LU15-09).
Authors: Myung-Ju Ahn, Jang Ho Cho, Jong-Mu Sun, Se-Hoon Lee, Jin Seok Ahn, Keunchil Park, Keon Uk Park, Eun Joo Kang, Yoon Hee Choi, Ki Hwan Kim, Ho Jung An, Hyun Woo Lee
Journal: Journal of Clinical Oncology (2018)

9050 Background: Approximately 10% of EGFR mutants harbor uncommon mutations, which represent a heterogeneous group of rare molecular alterations within exons 18-21 and the sensitivity to EGFR TKIs is variable. Osimertinib is a potent irreversible inhibitor of both sensitizing EGFR mutation and T790M. In preclinical data, the potency of osimertinib against uncommon EGFR mutants other than exon 20 insertion was fairly good. Here we present the efficacy and safety of osimertinib in patients with uncommon EGFR mutation positive NSCLC. Methods: Patients with histologically confirmed metastatic or recurrent NSCLC with activating EGFR mutation other than exon 19 deletion, L858R, T790M and insertion in exon 20 were eligible. Patients received 80mg of osimertinib per oral daily until progression or unacceptable toxicity. Response was assessed every 8 weeks by investigator. The trial was registered with ClinicalTrials.gov, number NCT03424759. Results: Between Mar 2016 and Oct 2017, 36 patients were enrolled. Median age was 59.5, 61% male, 44% never smoker, 97% adenocarcinoma. 61% of patients were treated as first-line therapy. The most common mutations are G719A/C/D/S/X (19, 52.8%) followed by L861Q (9, 25%), S7681 (8, 22%), and others (4, 11%). The overall response rate was 50.0% (95% CI 32.8-67.2) and DCR was 88.9% (95% CI 78.1-99.7). Seven patients (77.8%) with L861Q mutation achieved partial response; 10 (52.6%) with G719A/C/D/S/X mutation; three (37.5%) with S768I mutation. At data cutoff (Nov, 2017), the median PFS was 9.5 months (range 1.0-20.1) and median duration of response was 7.0 months (95% CI 4.7-9.3). The most common adverse events were rash (n = 11, 30.6%), anorexia (n = 8, 22.2%), and diarrhea (n = 7, 19.4%). Grade 3 or 4 AEs were reported in 8 of 36 patients (22%), but all of AEs were manageable. Conclusions: Osimertinib showed highly active and durable in NSCLC patients harboring uncommon EGFR mutation with manageable safety profile, consistent with previous reports. Further analysis will be updated. Clinical trial information: NCT03424759.
Abstract P348: Association Between Sleep Apnea and Blood Pressure Control Among African-Americans, the Jackson Heart Study
Authors: Dayna A Johnson, Stephen J Thomas, Marwah Abdalla, Yuichiro Yano, Na Guo, Michael Rueschman, Rikki Tanner, James Wilson, Murray Mittleman, David A Calhoun, Susan Redline
Journal: Circulation (2018)

Background: African-Americans have the highest prevalence of elevated blood pressure (BP) and poorer BP control than other racial/ethnic groups in the US. Untreated sleep apnea, common among minority populations, may explain the high prevalence of uncontrolled BP. We studied the association of objective measurements of sleep apnea severity with resistant hypertension and uncontrolled BP among African-Americans in the Jackson Heart Study (JHS) Sleep Ancillary study. Methods: Between 2012 and 2016, JHS participants (N=913) underwent an in-home sleep apnea study (measuring nasal pressure, abdominal and thoracic inductance plethysmography, oximetry, position, ECG); resting blood pressure; anthropometry; and completed questionnaires. Sleep apnea was defined as an apnea-hypopnea index &gt; 15 and nocturnal hypoxemia was quantified as % sleep time &lt;90% oxyhemoglobin saturation (%Sat&lt;90%). Elevated BP was defined as systolic BP ≥ 140 mmHg or diastolic BP &gt; 90mmHg. Controlled BP was defined as systolic BP &lt;140mmHg or diastolic BP &lt;90mmHg. Uncontrolled BP was defined as having elevated BP with use of &lt; 2 antihypertensive medications. Resistant hypertension was defined as having elevated BP while on 3-4 antihypertensive medications with one being a diuretic; or use of &gt; 4 antihypertensive medications. The study sample was limited to individuals with prevalent hypertension (N=613). Multinomial models were fit to determine the association between sleep apnea severity and resistant hypertension or uncontrolled BP (vs. controlled BP) adjusted for age, sex, education, smoking status, obesity (body mass index&gt;30) and diabetes. Results: The study sample had a mean age of 54.8 years, were predominately female (69.8%), obese (57.8%), and college educated (52.7%). Approximately 40.5% had sleep apnea, which was untreated in 95% of individuals. Among the sample, 25.4% had uncontrolled BP and 4.9% were classified as resistant hypertension. After adjustment for confounders, individuals with sleep apnea had a 2.6-fold higher odds of resistant hypertension (95% confidence interval: 1.1, 5.9). A standard deviation higher %Sat&lt;90% was associated with a 41% higher odds (1.1, 1.8) of resistant hypertension after adjustment for covariates. Sleep apnea and %Sat&lt;90% were not related to uncontrolled BP. Conclusion: Among our sample of African-Americans in the JHS, sleep apnea was related to resistant hypertension but not uncontrolled BP. The study identifies the high burden of untreated sleep apnea in African-Americans and its association with resistant hypertension, a significant risk factor for stroke and heart disease. Research is needed on the impact of treating sleep apnea as a strategy for decreasing resistant hypertension, and thus, narrowing cardiovascular health disparities.