tbuckley/cabot-search huggingface dataset:
Identification of leiomyosarcoma circulating tumor DNA through ultra-low passage whole genome sequencing and correlation with tumor burden: A pilot experience.
Authors: Matthew Louis Hemming, Kelly S Klega, Kate E Acker, Anwesha Nag, Aaron Thorner, Michael Nathenson, Chandrajit P. Raut, Brian D. Crompton, Suzanne George
Journal: Journal of Clinical Oncology (2018)

11565 Background: Detection of circulating tumor DNA (ctDNA) has emerged as a new approach for identifying oncogenic mutations, measuring disease burden, clinical prognostication, and assessing response to therapy. Most ctDNA assays detect single-nucleotide variants (SNVs) that are highly recurrent in carcinomas. Though there are few recurrent SNVs in leiomyosarcoma (LMS), LMS is characterized by numerous chromosomal copy-number alterations (CNAs). We therefore evaluated plasma from patients with LMS for the presence of ctDNA using an ultra-low passage whole genome sequencing (ULP-WGS) approach designed to detect somatic chromosomal CNAs. Methods: We identified 30 tumor/plasma pairs from patients with advanced LMS. Ten pairs have undergone ULP-WGS, with an additional 20 pairs currently in process. Of the 10 pairs evaluated, 7 were of uterine and 3 of extrauterine origin. DNA from plasma samples was subjected to ULP-WGS and compared to tumor DNA. Differences in genome-wide sequencing coverage were used to identify chromosomal amplification or deletion and ichorCNA software was used to estimate tumor fraction of each sample. Identified CNAs from tumor specimens were used to confirm the specificity of ULP-WGS to detect CNAs in plasma. Clinical data were reviewed to assess disease burden and progression status. Results: ctDNA was identified in 5 of 10 cases including 5 out of 6 patients with progressive disease. None of the patients with no evidence of disease (NED) or with stable disease had detectable ctDNA. We identified ctDNA in patients with both metastatic uterine LMS and extrauterine LMS. CNAs in plasma correlated with CNAs detected in matched tumor samples. Conclusions: Identification of plasma ctDNA by ULP-WGS is feasible in patients with advanced LMS and correlates with tumor burden/progression. An additional 20 cases will be presented. These preliminary results support further investigation of ULP-WGS as a novel blood-based assessment of tumor burden in LMS. Future experiments will assess the utility of ULP-WGS in detecting residual disease following surgery, surveillance for disease recurrence, and monitoring response to therapy.
The PI3K-Akt signaling leads to synergy of erlotinib and crizotinib in wild-type NSCLC.
Authors: Christian Diego Rolfo, Nele Van Der Steen, Patrick Pauwels, Pablo Reclusa, Godefridus J. Peters, Elisa Giovannetti
Journal: Journal of Clinical Oncology (2017)

e20043 Background: Targeted therapies caused a revolution in treatment of non-small cell lung cancer (NSCLC). Response to Epidermal Growth Factor Receptor such as erlotinib, can be predicted by the presence of sensitizing mutations in EGFR. In case of cMET, amplification or exon 14 skipping serve as biomarkers for response to cMET-TKIs, crizotinib. Methods: In this study, we investigated the combination of erlotinib and crizotinib on several squamous NSCLC cell lines wild-type for EGFR and cMET. Growth inhibition was determined using the sulforhodamine B-assay. Combination indexes (CI) were calculated based on the method of Chou and Talalay. A CI below 0.8 was considered synergistic, between 0.8 and 1.2 was considered additive and above 1.2 was considered antagonistic. The influence of treatment on the cell cycle, cell migration, 3D cell cultures and phosphorylation was studied. Results: The H1703 cell line gave an antagonistic (CI = 1.20±0.15), the Calu1 (CI = 0.81±0.04), H520 (CI = 0.87±0.06) and SKMES1 (CI = 0.81±0.02) were additive and LUDLU (CI = 0.39±0.07) was synergistic. A G1 phase arrest occurred after treatment with erlotinib (38 to 76%), whereas crizotinib caused a G2/M phase arrest (13 to 64%). In the combination, the effect of crizotinib was dominant (13 to 52%). A decrease in p-ERK1/2 (Thr202/204), p-PRAS40 (Thr246) and p-GSK3 β (Ser9) was observed. Phospho-PRAS40 showed a decrease after treatment with erlotinib or crizotinib, whereas combination treatment almost abolished p-PRAS40. In the SKMES1 cell line, p-PRAS40 only decreased after the combination, whereas H1703 cells showed no change in p-PRAS40 levels. Phospho-PRAS40 activity is strongly linked to PI3K/Akt signaling. Her3 is able to heterodimerize both with EGFR and cMET, thus activating downstream PI3K/Akt signaling. No expression of Her3 in the antagonistic cell line was detected. In the LUDLU, levels of p-Her3 were not detectable after erlotinib treatment and in the combination, whereas in the SKMES1 levels of p-Her3 slightly decreased only after combination treatment. Conclusions: To conclude, the simultaneous inhibition of both EGFR and cMET leads to a strong inhibition of PI3K/Akt signaling, leading to synergy in the LUDLU wild-type squamous NSCLC cells.
TCT-336 Transfemoral TAVR Treatment of Failing Aortic Valve Bioprostheses - Mid Term Results and Outcome
Authors: Felix Woitek, Georg Stachel, Stephan Haussig, Norman Mangner, Philipp Kiefer, Sergey Leontyev, David Holzhey, Michael Borger, Holger Thiele, Axel Linke
Journal: Journal of the American College of Cardiology (2018)
Outcomes of children with hereditary medullary thyroid carcinoma (MTC) treated with vandetanib.
Authors: Ira Lignugaris Kraft, Srivandana Akshintala, Claudia Derse-Anthony, Seth M. Steinberg, David J. Venzon, Eva Dombi, Steven G. Waguespack, Oxana Borisovna Kapustina, Elizabeth Fox, Frank M. Balis, John Frederick Shern, John Glod, Brigitte C. Widemann
Journal: Journal of Clinical Oncology (2017)

10540 Background: Vandetanib is well tolerated and active in children with advanced or metastatic hereditary MTC (NCT00514046) [data cutoff 7/2011; Clin Cancer Res. 2013 Aug 1;19(15):4239-48]. We report outcomes as of 1/2017. Methods: We monitored toxicities, RECISTv1.0, carcinoembryonic antigen (CEA), and calcitonin (CT) response. Patients (pts) removed from the vandetanib trial were followed on a natural history study (NCT01660984). Results: Of 17 pts (8 male, age 13 years (9-17)*) enrolled, 1 was lost to follow-up. Of the 16 pts analyzed, 15 had a RET p.M918T germline mutation. The duration of vandetanib therapy was 5.6 years (0.1-9.2+) with treatment ongoing in 8 pts. Best response was partial response (PR) in 10, stable disease (SD) in 5, and progressive disease (PD) in 1 pt. Time to achieve PR (n = 10) was 0.6 years (0.4-2.4). Time to best response (n = 16) was 1.5 years (0.1-4.1). Duration of response was 5.1 years (1.3-8.6+) in pts with PR and 4.8 years (0.6-7.3+) in pts with SD. Seven of 8 pts with PD subsequently received sunitinib, sorafenib, and/or cabozantinib. Disease progression occurred as increase in target (n = 2), non-target/new lesions (n = 5), or CT/CEA (n = 1). Six pts died from disease 2.1 years (0.4-4.3) after stopping vandetanib. Progression free survival was 6.2 years (95% CI 3.0-na) and overall survival was 7.9 years (95% CI 5.9-na).Pts had no difference in enrollment age, baseline CT/CEA, or tumor size per response categories (n = 16). Rate of CEA/CT decrease during initial 4 months of treatment was not associated with PR/SD compared to PD (n = 16). While on vandetanib, 6 pts with PD had CEA or CT doubling time (DT) of &lt; 2 years within 1 year prior to PD. All pts with ongoing PR/SD had CEA and CT DT &gt; 2 years while on vandetanib. No pts came off treatment for toxicity. Dose reductions occurred in 8 pts for grade (gr) 2 weight loss (n = 2), palpitations (n = 1), arrhythmia (n = 1), elevated creatinine (n = 1), diarrhea (n = 2), and gr 3 constipation (n = 1). Conclusions: Many children with hereditary MTC sustained PR/SD on vandetanib. However, half ultimately developed PD and died from disease despite treatment with other targeted therapies. CEA/CT DT &lt; 2 years within 1 year of progression on vandetanib may be associated with PD. *Median (range)
Comparing surgical staging methods for type II endometrial cancers.
Authors: Leda Portia A. Gattoc, Hyo K. Park, Laura Carney, Shashank Srivastava, Monica Chiu, Mukti Patel, Ira Seth Winer
Journal: Journal of Clinical Oncology (2017)

e17107 Background: Type II endometrial cancers account for 10% of endoemetrial cancers, but their aggresive nature account for a significant proportion of the morbidity and mortality. The goal of this study was to compare outcomes type II endometrial cancer patients who underwent staging via laparotomy vs. minimally invasive approach (MIS). Methods: All patients who underwent surgery for Type II endometrial cancer at two cancer centers in Detroit MI from January 2005 and December 2015 were reviewed. Endometrioid histology and those who never had surgery were excluded. Clinical, demographic characteristics, surgical outcomes and progression free survival were examined using univariate and multivariable analysis, Kaplan-Meier estimates and Cox proportional hazards regression. Results: A total of 249 patients were included, 193 underwent laparotomy, and 58 MIS, including laparoscopic or robotic surgery. The majority had stage I disease (IA, 104 [41.3%] and IB, 20[7.9%]). Stages II, III, and IV were identified in 18 (7.1%), 79 (31.6%), and 31 (12.4%) respectively. Multivariate analysis demonstrated being African American (OR 3.43; 95%CI 1.64-7.15), having mixed histology(OR 2.54; 95% CI 1.02-6.32), and stage III-IV disease (OR 2.20; 95%CI 1.04-4.67) was associated with undergoing laparotomy. Higher perioperative complications, EBL &gt;250 cc and blood transfusion were associated with laparotomy. Higher lymph node yield was associated with MIS approaches vs. laparotomy (26 vs. 14 p =&lt;0.001). Recurrence rate was 38 % for the laparotomy group and 19% for MIS. There was no difference in 3 year-PFS after controlling for age, race, procedure, histology, stage and adjuvant therapy. There was no difference in overall survival between laparotomy and MIS for type II endometrial cancers. Conclusions: Being African American race, having mixed histology and stage were associated with undergoing laparotomy for type II endometrial cancers. MIS approaches offered less morbidity and ability to complete staging. However, patient selection likely played a role in this given earlier stage of these cancers. The route of surgery was not associated with PFS or OS, suggesting that MIS approach should be considered especially for ealry stage disease.
TCT-544 A novel physiological assessment of myocardial mass volume
Authors: Tadashi Murai, Tim van de Hoef, Thomas van den Boogert, Gilbert Wijntjens, Valérie Stegehuis, MAuro Echavarria, Masahiro Hoshino, Taishi Yonetsu, Nils Planken, Jose PS. Henriques, Javier Escaned, Tsunekazu Kakuta, Jan Piek
Journal: Journal of the American College of Cardiology (2018)
Molecular features underlying response to neoadjuvant gemcitabine, cisplatin, and sorafenib (S-GC) in muscle-invasive urothelial bladder carcinoma (MIBC): Insights for trials of new agents combined with chemotherapy in the field.
Authors: Andrea Necchi, Daniele Raggi, Adele Busico, Loris De Cecco, Patrizia Giannatempo, Nicola Nicolai, Luigi Piva, Davide Biasoni, Mario Catanzaro, Tullio Torelli, Silvia Stagni, Giuseppina Calareso, Elena Togliardi, Maurizio Colecchia, Luigi Mariani, Roberto Salvioni, Alessandro Paoli, Maria Grazia Daidone, Marialuisa Sensi, Federica Perrone
Journal: Journal of Clinical Oncology (2017)

e16018 Background: S-GC neoadjuvant chemotherapy (NACT) was active in a phase 2 trial in MIBC, showing a response rate (downstaging to pT &lt; 2) of 54.3% in 46 pts within a single-arm, phase 2 trial ( Necchi et al, GU ASCO 2017). The addition of S to GC may help investigators unravelling key molecular features underlying response in MIBC. Methods: Analyses were made on pre- and post-treatment TURB and cystectomy (Cy) specimens (10µm sections) and matched germline DNA of 29/46 pts. Analyses included measurements of ERCC1 (by immunohistochemistry, IHC) on TURB specimens, baseline circulating VEGF levels (ELISA), copy number variations (CNV, Affymetrix), and next generation sequencing (NGS, custom gene panels through the Ion AmpliSeq Library Kit2.0™ and the Ion Torrent Personal Genome Machine™ platform). Results: We analyzed TURB samples from 15 responders (R) and 4 non-R (NR). An additional 10 Cy samples were used for NR. Baseline VEGF levels were not associated with PFS or OS on univariable analyses (p = 0.943 and p = 0.669, respectively). Differences in R vs. NR pts were found according to CNVs and NGS. CN gains on regions of chromosome (chr) 18 and 20 and loss in chr 5 were found in 56-60% of R and in none of the NR. Gains on regions of chr 3 and losses in chr 1 and 20 were more frequent in the NR ( &gt; 50%) vs. R ( &lt; 20%). The median number of somatic mutations (mut) per sample was 3 (range, 0-19). Missense mut in DNA-repair genes ( POLK; FANCM; PRKDC; BLM; MSH2; MSH6; RAD50) were found in 63.6% R vs 16.7% NR, in RAS-RAF pathway genes ( CDKN2A; RAC1; KRAS; NF1) in 45.4% vs 7.1%, in chromatin-remodelling genes ( ARID1A; ARID2; KDM5C; SMARCA4; ATRX; KMT2C; DAXX; SETD2) in 54.5% vs 16.7%, and in HER-family genes in R only (36.4%). ERCC1 IHC expression was found in 55.6% R vs 93.3% NR (p = 0.047). Conclusions: We identified distinct molecular features of R vs NR to S-GC in MIBC. These features may be linked to a potentially-additive effect of S and CT. The identification of the targets of CNVs will further elucidate the underlying biology. These results may help developing personalized medicine in MIBC with new more potent targeted agents with CT. Clinical trial information: NCT01222676.
Real world treatment (tx) patterns and total cost of care among patients (pts) receiving <i>nab</i>-paclitaxel+carboplatin (<i>nab</i>-P/C) versus sb-paclitaxel+carboplatin (sb-P/C) as first line (1L) tx for metastatic non-small cell lung cancer (mNSCLC).
Authors: Manali I. Patel, Manish Patel, Quanhong Ni
Journal: Journal of Clinical Oncology (2016)

e18274 Background: nab-P/C and sb-P/C are both recommended as category 1 1L tx options for mNSCLC by NCCN; however there is limited data comparing the total cost of care between the two.This study evaluated differences in real-world tx patterns and total costs among mNSCLC pts treated with nab-P/C and sb-P/C. Methods: A retrospective study was conducted with Marketscan claims data. mNSCLC pts ( ≥ 18 years) receiving ≥ 2 doses of nab-P/C or sb-P/C between 2013-2014 and ≥ 30 days of follow-up were included. Time to treatment discontinuation (TTD) and estimated survival (ES) were calculated by the Kaplan-Meier method. Total cost (including treatment drugs) per pt per month over duration of 1L and ES and costs for supportive care (SC) during 1L (i.e. GCSF, ESA, fluids and electrolytes (F&E), antiemetics) were compared. Results: A total of 131 pts received weekly nab-P/C, while 356 received sb-P/C every 3 weeks. Pts on nab-P/C were older (mean age: 65.2 v 61.8; p < 0.01). More sb-P/C pts received triplet therapy with bevacizumab (48% v 18%; p < 0.01). Median TTD was significantly longer for nab-P/C v sb-P/C (3.5 v 2.4 months (mos), p < 0.01). Median ES was not significantly different (nab-P/C 10.3; sb-P/C 9.8 mos; p = 0.65). Mean total cost per month while on 1L tx was not significantly different between nab-P/C and sb-P/C ($22,610 v $22,512; p = 0.99). Monthly SC costs were significantly lower for nab-P/C v sb-P/C ($2,220 v $3,975; p < 0.01), primarily due to lower costs for GCSF ($1,035 v $2,853; p = 0.03) and F&E ($65 v $379; p < 0.01). Costs for ESA ($252 v $74; p = 0.16) and antiemetics ($844 v $660; p = 0.15) were not statistically different between nab-P/C and sb-P/C. Total costs per month over the ES decreased for both cohorts compared to costs over 1L, but were not statistically different (nab-P/C $17,604; sb-P/C $17,901; p = 0.79). Conclusions: Compared to sb-P/C, pts on nab-P/C had longer TTD and similar ES despite more use of bevacizumab for pts on sb-P/C. Monthly costs for SC were significantly lower for pts while on nab-P/C. Monthly total costs over ES were lower for nab-P/C, but not statistically significant.
Outcomes of de novo CD5+ diffuse large b-cell lymphoma (DLBCL) in the rituximab (R) era.
Authors: Bei Hu, Sanam Loghavi, Luis Fayad, Mansoor Noorani, Nathan Hale Fowler, Fredrick B. Hagemeister, Hun Ju Lee, Loretta J. Nastoupil, Sattva Swarup Neelapu, Michelle A. Fanale, Felipe Samaniego, Francesco Turturro, Michael Wang, Richard Eric Davis, Jason R. Westin, L Jeffrey Medeiros, Yasuhiro Oki
Journal: Journal of Clinical Oncology (2017)

e19019 Background: De novo CD5+ DLBCL is associated with poor prognosis. Methods: We retrospectively reviewed the MD Anderson Lymphoma Outcome Database and identified 104 patients (pts) with de novo CD5+ DLBCL diagnosed between 2001-2016. We excluded primary CNS lymphoma and Richter’s transformation. Results: Median age was 62 (range 29-96); 55% were male. Most (71%) pts had advanced stage at diagnosis, with 55% being Stage IV. Eighty percent (n = 79) had extranodal disease at presentation with bone/bone marrow being the most common site (40%); central nervous involvement was seen in 5%. Two-thirds had elevated LDH; 37% had B symptoms on presentation. ECOG PS was ≥2 in 26% of pts; beta-2 microglobulin was elevated in 68%. Of the 77 pts with IPI score, 21% (n = 16), 23% (n = 18), 26% (n = 20), and 30% (n = 23) were considered low, low-intermediate, high-intermediate, and high risk, respectively. In the diagnostic specimen, median Ki67 was 85%. Majority were non-GCB by Han’s criteria (n = 47 of 77). Two pts were double-hit lymphoma. All received R-containing regimens for primary therapy, including RCHOP (n = 64), dose-adjusted R-EPOCH (n = 24), R-HyperCVAD (n = 6), and other (n = 10). Prophylactic intrathecal chemotherapy use was 35%. Sixty-eight (65%) pts achieved complete response (CR) with primary therapy. Two pts underwent frontline autologous stem cell transplant. Median PFS duration was 28 months (mo) (95% CI: 10-27). Median OS duration was 112 mo (95% CI: 10-214). Pts with primary refractory disease had the worst OS duration of 14 mo. Pts with relapse within 1 year of achieving CR fared no better with median OS of 22 mo. PFS and OS were not significantly different by choice of primary therapy. By multivariate analysis using Cox proportional hazard model, male gender (HR = 3.0, 95% CI: 1.1-8.1, p = 0.029) and high IPI (HR = 2.5, 95% CI: 1.4-4.3, p = 0.001) were associated with shorter PFS. Only IPI score was significantly associated with worse OS (HR = 3.0, 95% CI: 1.6-5.7, p = 0.001). Conclusions: De novo CD5+ DLBCL is frequently associated with extranodal presentation and poor outcome with R-containing intensive chemotherapy. IPI remains the most significant prognostic factor for worse PFS and OS. There is clearly an unmet need for novel treatment for this disease.
RUNX1 Mutations Lead to a Myeloid Differentiation Block in Association with Enhanced Proliferation By Altering the RUNX1 Transcriptional Program
Authors: Mylene Gerritsen, Esther Tijchon, Guoqiang Yi, Jorren Kuster, Jan Jacob Schuringa, Joost H. A. Martens, Edo Vellenga
Journal: Blood (2017)
Phase II study of amrubicin plus erlotinib in previously treated, advanced non-small cell lung cancer with wild-type EGFR (TORG1320).
Authors: Shinobu Hosokawa, Akihiro Bessho, Sakiko Otani, Jiichiro Sasaki, Satoshi Igawa, Yoshiro Nakahara, Nobuaki Fukamatsu, Takashi Kasai, Tomohide Sugiyama, Nobuhiko Seki, Yukiko Nakamura, Takaaki Tokito, Noriyuki Masuda, Koshiro Watanabe
Journal: Journal of Clinical Oncology (2017)

e20677 Background: Amrubicin (AMR) is a totally synthetic 9-aminoanthracycline and clinically active against non-small cell lung cancer (NSCLC). We found that the combination of AMR and erlotinib (ERL) had significant synergistic effect on NSCLC cell line with wild-type EGFR in vitro. We conducted a phase I study of AMR and ERL combination therapy in previously treated patients with advanced NSCLC, and have already reported the safety and the effectiveness. Furthermore we observed a high response rate of 33% in EGFR wild-type NSCLC. Methods: We conducted a multi-center, single-arm phase II trial to evaluate the efficacy of AMR and ERL combination therapy in patients with previously treated, advanced NSCLC, PS 0-1, and aged &lt; 75 years, EGFR wild type. Patients were treated at 3weeks intervals with AMR(35mg/m 2 , intravenous injection on days 1-3) plus ERL(100mg/day, once daily on days 1-21). The primary endpoint is progression free survival (PFS). Secondary endpoints are response rate (RR), disease control rate (DCR), time to treatment failure (TTF), overall survival (OS), and toxicity. The concentration of trough ERL was measured after first cycle of treatment as additional investigation. Results: From June 2013 to July 2016, 25 patients were enrolled in this trial. The PFS according to the central test was 3.6 months (95%CI 2.1 - 5.1). The RR and the DCR were 24.0% and 64.0%, respectively. We observed grade 3 or 4 hematological toxicities such as leukopenia (68%), neutropenia (72%), anemia (8%) and febrile neutropenia (12%). The grade 3 or 4 non-hematological toxicities were anorexia (12%), oral mucositis (12%) and rash (8%). We had no treatment related death in this study. Conclusions: The PFS of AMR and ERL combination therapy in this study was superior to that of AMR monotherapy in historical setting. This combination therapy might be an option for previously treated NSCLC patients without a driver oncogene mutation. Clinical trial information: UMIN 000010582. Clinical trial information: UMIN 000010582.
Constitutive activation of mTOR pathways in renal cell carcinoma arising in dialyzed patients.
Authors: Ryuichi Mizuno, Shuji Mikami, Kimiharu Takamatsu, Nozomi Hayakawa, Takeo Kosaka, Eiji Kikuchi, Mototsugu Oya
Journal: Journal of Clinical Oncology (2018)

e16565 Background: Patients with end-stage renal disease (ESRD) requiring hemodialysis (HD) have a higher risk of renal cell carcinoma (RCC) than the general population, and long-term dialysis therapy is reportedly associated with a high incidence of RCC, suggesting that long-term exposure to uremic toxicity might cause genomic damage in native kidneys tissues. The aims of the present study were to investigate the activation pathway of RCC arising in HD patients (HD-RCC). Methods: We used the whole genome sequencing methods on primary tumor samples of HD-RCC arising in 3 HD patients. We collected sequencing data of clear cell RCC (ccRCC) from the TCGA website (https://portal.gdc.cancer.gov/) and compared our sequencing data of HD-RCC. We also collected 21 HD-RCC samples to evaluate the activation of mTOR pathway by immunostaining. Results: In 3 samples from HD-RCC, any mutation of the five high-confidence driver genes (VHL, BAP1, SETD2, PTEN and KDM5C) reported in ccRCC was not detected. In 1case, TSC1 mutation was detected. Since genes of the mTOR signaling pathway have drawn great attention as key targets for cancer treatment, the activation of mTOR pathway was determined by evaluating the phosphorylation status of mTOR, P70S6K and 4E-BP1. In 21cases of HD-RCC, mTOR, P70S6K and 4E-BP1 were activated in 18/21 (85.7%), 14/21 (66.7%), 12/21 (57.1%), respectively. Conclusions: Any mutation of putative driver genes of ccRCC was not detected in HD-RCC samples. Instead, constitutive activation of mTOR pathways was demonstrated in HD-RCC patients.