tbuckley/cabot-search huggingface dataset:
Preoperative chemoradiotherapy (QT-RT) with capecitabine and oxaliplatin (CAPOX) or capecitabine alone (CAP) in patients (PTS) with locally advanced rectal cancer (LARC).
Authors: Ines Marrodan, Itziar Rubio, Aitziber Buque, Aintzane Sancho, Natalia Fuente, Sergio Carrera, Mikel Arruti, Joan Manel Mane, Eddy Isabel Gutierrez, Eluska Iruarrizaga, Eider Azkona, Guillermo Lopez-Vivanco
Journal: Journal of Clinical Oncology (2013)

e14712 Background: Preoperative concomitant QT-RT has shown to improve sphincter preservation and local control in LARC. We analyzed two cohorts of pts diagnosed of LARC treated with QT-RT with CAP or CAPOX. Methods: Pts with LARC (T3-T4 and/or N+) were treated with pelvic radiotherapy (45Gy in 25 fractions) concomitant with oxaliplatin (50mg/m2 day 1, 8, 22 and 29) and capecitabine (1650mg/m2 on days 1 to 14 and 22 to 35) or CAP (825mg/m2 bid for 5 days/week). Surgery was scheduled 6 weeks after completion QT-RT. Main end points assessed were: toxicity of preoperative chemotherapy, rate of sphincter preservation, pathological complete response (pCR) rate, and progression-free survival (PFS). Results: From Aug 2002 to Nov 2012, 254 pts with LARC were included; 53 pts received preoperative chemotherapy with CAP (cohort A) and 201 pts with CAPOX (cohort B). Median age: 65. Pts characteristics in cohort A: ECOG 0/1/2: 13/35/5; upper/mid/distal rectum 5/25/23; stage II/III 10/43. Pts characteristics in cohort B: ECOG 0/1/2: 48/149/4; upper/mid/distal rectum 29/105/67; stage II/III 27/174. 51 pts in cohort A (96.2%) and 192 (95%) in cohort B received full dose of preoperative QT-RT. Main toxicities in cohort A were diarrhea grade 2/3: 2/3 and neutropenia grade 2/3: 1/0; in cohort B were diarrhea grade 2/3: 42/24, neutropenia grade 2/3: 2/1 and neurotoxicity grade 1/2: 94/7. Surgery: 53 pts (100%) in cohort A and 198 pts (98.5%) in cohort B. Sphincter preservation and R0 resections were achieved in 58% pts and 98% pts respectively in cohort A, and 62% pts and 91.5% pts in cohort B. pCR was achieved in 11% pts in cohort A and 17% pts in cohort B. 3-year PFS and overall survival were 62% and 82% respectively in cohort A, and 75% and 83% in cohort B. Adding oxaliplatin in pts cT4/N- or N+ does not improve PFS (p=0.73). Downstaging in cohort A and B was achieved in 69.8% pts and 65% pts respectively. Conclusions: Combination QT-RT based in CAP or CAPOX is a well tolerated regimen and achieved encouring rates of pCR, R0 resection, sphincter preservation and tumor downstaging without differences in PFS in high risk pts with LARC.
Nintedanib (BIBF 1120) plus docetaxel in NSCLC patients progressing after one prior chemotherapy regimen: Results of Lume-Lung 1, a randomized, double-blind, phase III trial.
Authors: Martin Reck, Rolf Kaiser, Anders Mellemgaard, Jean Yves Douillard, Sergey Orlov, Maciej Jerzy Krzakowski, Joachim Von Pawel, Maya Gottfried, Igor Bondarenko, Meilin Liao, Jose Barrueco, Birgit Gaschler-Markefski, Silvia Novello
Journal: Journal of Clinical Oncology (2013)

LBA8011 The full, final text of this abstract will be available at abstract.asco.org at 7:30 AM (EDT) on Monday, June 3, 2013, and in the Annual Meeting Proceedings online supplement to the June 20, 2013, issue of Journal of Clinical Oncology. Onsite at the Meeting, this abstract will be printed in the Monday edition of ASCO Daily News.
ROR1 mRNA expression in EGFR-mutant non-small-cell lung cancer (NSCLC) patients (p) with the T790M mutation: A potential therapeutic target.
Authors: Niki Karachaliou, Ana Drozdowskyj, Carlota Costa, Miguel Angel Molina-Vila, Ana Gimenez Capitan, Alain Vergnenegre, Bartomeu Massuti, Teresa Moran, Margarita Majem, Enriqueta Felip, Enric Carcereny Costa, M. Rosario Garcia-Campelo, Santiago Viteri Ramirez, Cordula Nicole Heidecke, Roger Estrada-Tejedor, Jordi Teixido, Trever Grant Bivona, Petros Giannikopoulos, Mayumi Ono, Rafael Rosell
Journal: Journal of Clinical Oncology (2013)

11027 Background: Progression-free survival (PFS) is short in NSCLC driven by EGFR mutations treated with erlotinib alone, due to crosstalk with other signaling pathways that can cause secondary dependency. ROR1 knockdown inhibited the growth of NCI-H1975 cells (with EGFR L858R and T790M mutations). A pro-survival function for ROR1/MEK/ERK signaling has been demonstrated, with cooperation with AKT. In a subset of 95 p in the EURTAC trial (clinicaltrials.gov NCT00446225), 65% had pre-treatment T790M mutations. We have assessed ROR1 expression in 45 of these 95 p. Methods: The T790M mutation was determined by Taqman with a PNA to inhibit amplification of the wild-type (wt) allele. Tumor samples were run in octuplicates; this method can detect 1 mutated allele among 10,000 wt alleles. ROR1 mRNA expression was examined by quantitative RT-PCR and categorized by terciles. p were classified as having low/intermediate or high ROR1 expression. The impact of ROR1 expression on outcome was examined in all 45 p and in a subset of 15 p with concomitant T790M mutations. Results: Median age 65; 68.9% female; 57.8% never-smokers; 95.6% ECOG PS &lt;2; 91.1% adenocarcinoma; 68.9% exon 19 deletion. No differences in baseline characteristics were observed according to ROR1 expression levels. 24 p (53.3%) were treated with erlotinib and 21 p (46.7%) with chemotherapy. 10 (41.7%) erlotinib-treated p and 6 (28.6%) chemotherapy-treated p had ROR1 mRNA levels in the top tercile. Among erlotinib-treated p, response rate was 40% for p with high ROR1 levels vs 71.4% for p with low/intermediate levels (P=0.0918). Among chemotherapy-treated p, only p with low ROR1 levels responded (6.7%). PFS was 11.8 months (m) for erlotinib-treated p with low/intermediate ROR1 levels vs 5.8 m for p with high levels. PFS for chemotherapy-treated p was 5.6 and 9 m, respectively (P=0.033). Among 15 erlotinib-treated p with concomitant T790M mutations, PFS was10.8 m for p with low/intermediate ROR1 levels vs 2.7 for p with high levels (P=0.0174). Conclusions: HighROR1 expression significantly limits PFS in p with T790M mutations. ROR1-directed therapies can enhance the efficacy of erlotinib in EGFR-mutant NSCLC p overexpressing ROR1. Clinical trial information: NCT00446225.
Reduced-Intensity Stem Cell Transplantation Is a Promising Therapeutic Strategy for Pediatric Patients with Wiskott-Aldrich Syndrome: A Case Series of 7 Patients with a Uniform Reduced-Intensity Conditioning
Authors: Yoshihiro Gocho, Katsuyoshi Koh, Motohiro Kato, Yoshihisa Nagatoshi, Junko Takita, Ryoji Hanada, Kohmei Ida
Journal: Blood (2011)
Abstract 11169: Whole Exome Sequencing in Subjects With Mendelian Form of Primary Severe Hypertriglyceridemia
Authors: Hayato Tada, Akihiro Nomura, Masa-aki Kawashiri, Atsushi Nohara, Akihiro Inazu, Hiroshi Mabuchi, Sekar Kathiresan, Masakazu Yamagishi
Journal: Circulation (2016)

Background: Few data exist regarding clinical application of whole exome sequencing (WES) for the molecular diagnosis of the subjects with Mendelian form of primary severe hypertriglyceridemia (HTG). Methods: WES was performed on 28 individuals exhibiting severe HTG (≥ 1,000 mg/dl) without any transient causes (15 men, mean age 42 ± 20 yr, median triglyceride 1,756 mg/dl [interquartile range 1,288-2,443]) followed by recessive and dominant inheritance modeling in known monogenic HTG genes and disease-network candidate analysis gene ranking to identify a causative mutation(s), including novel underlying genetic mechanism for severe HTG. Results: Using our schema, we identified possible causative mutation(s) in 14 individuals (50%). Among them, we identified 2 individuals with lipoprotein lipase (LPL) deficiency with double mutations in LPL gene, and 2 individuals with a heterozygous mutation carrier in LPL gene. Moreover, we identified one individual harboring a double mutations in LPL gene and APOA5 gene. Also we identified one individual with a heterozygous mutation in lipase maturation factor 1 (LMF1) gene, which is rarer form of familial hyperchylomicronemia, and 2 individuals with type 3 hyperlipidemia harboring mutations in APOE gene, including novel ones. Interestingly, we also identified 6 other individuals harboring a deleterious mutation in cyclic AMP-responsive element-binding protein 3-like protein 3 (CREB3L3), MLX Interacting Protein-Like (MLXIPL), SLC25A40 genes, glucokinase regulatory protein (GCKR), possibly associated with this extreme phenotype. Conclusion: We identified potential causative mutations in 14 among 28 individuals (50%) with severe HTG within the coding region of the genes known to cause rare Mendelian dyslipidemias. Clinical WES is now feasible where molecular diagnoses could be made in such extreme cases, which could potentially provide appropriate therapies.
<i>ROS1 </i>rearrangement coexists with<i> EGFR </i>mutation in non-small-cell lung cancer.
Authors: Rui-lian Chen, Jin-Ji Yang, Xu-Chao Zhang, Na-na Lou, Huajun Chen, Qing Zhou, Jian Su, Weibang Guo, Jian-guang Chen, Haiyan Tu, Yueli Sun, Yi-Long Wu
Journal: Journal of Clinical Oncology (2015)

e19003 Background: C-ros oncogene 1 receptor tyrosine kinase (ROS1) is a newly identified gene-rearranged oncogenic receptor tyrosine kinase and patients seem to benefit from crizotinib treatment. We aim to evaluate the clinical characteristics and molecular profile of ROS1-rearranged patients with non-small-cell lung cancer (NSCLC). Methods: Between December 2013 and December 2014, we screened 708 NSCLC patients using reverse transcription Polymerase Chain Reaction (RT-PCR) assay and correlated ROS1 rearrangement status with clinical features. EGFR mutation was detected by DNA sequencing or ARMS. KRAS mutation and ALKrearrangement were tested by DNA sequencing and FISH respectively. Results: Of 708 NSCLC patients, ROS1 rearrangements were detected in 11 cases (1.6%).There was no significant difference in age (P= 0.74), gender (P= 0.54), stage (I-IIIA vs. IIIB-IV P= 0.74), histology (adenocarcinoma vs non-adenocarcinoma, P= 0.99) or T status (T0-2 vs. T3-4, P= 0.23) between patients with ROS positive and negative NSCLC. Compared with the ROS1 negative group, patients with ROS1 rearrangements were more likely to be never-smokers (P= 0.04). Nine (81.8%) of the 11 ROS1 positive patients were adenocarcinomas and 6 of them with acinar or solid adenocarcinoma patterns, while 2 were large-cell and sarcomatoid carcinoma. The frequency of ROS1 rearrangements was 2.5% (6/243) among EGFR/KARS/ALK triple negative NSCLCs. Among 4 cases harboring concomitant ROS1 rearrangement and EGFR mutation, there were 3 with EGFR exon 19 deletion and 1 with exon 20 insertion. Both two patients with advanced NSCLC harboring concomitant ROS1 rearrangement and EGFRexon 19 deletion achieved partial response after first-line gefitinib treatment. Conclusions: ROS1 rearrangement was identified in a small subgroup of NSCLC patients and predominantly existed in never-smokers. ROS1 screening in never-smokers with triple negative NSCLC might be an effective strategy.Advanced NSCLC patients withconcomitant ROS1 rearrangement and EGFR mutation responded to gefitinib.
Clinical activity and safety profile of TGR-1202, a novel once daily PI3Kδ inhibitor, in patients with CLL and B-cell lymphoma.
Authors: Howard A. Burris, Manish R. Patel, Timothy S. Fenske, Owen A. O'Connor, Changchun Deng, Danielle M. Brander, Martin Gutierrez, Suzanne Fields Jones, John G. Kuhn, Hari P. Miskin, Peter Sportelli, Swaroop V.S. Vakkalanka, Ian Flinn
Journal: Journal of Clinical Oncology (2015)

7069 Background: TGR-1202 is a novel, next generation PI3Kδ inhibitor which lacks the hepatotoxicity associated with other PI3Kδ inhibitors and is active in patients (pts) with advanced heme malignancies (ASH 2014). Herein we present updated safety and efficacy results from a Ph I study of TGR-1202 in pts with rel/ref CLL and B-cell lymphoma. Methods: TGR-1202 is administered orally once-daily following a 3+3 dose escalation design. Eligible pts have rel/ref B-cell non-Hodgkin lymphoma (NHL), chronic lymphocytic leukemia (CLL), or other B-cell malignancy and an ECOG PS ≤ 2. Endpoints: safety, PK/PD, and efficacy. Results: As of Feb 2015, 58 pts evaluable for safety including CLL, FL, Hodgkin’s (HL), DLBCL, MCL, and MZL. Median age 63 yo (range: 22-85), 72% male, ECOG 0/1/2: 19/38/1, median prior Tx: 3 (range: 1-14), 48% refractory to prior Tx. Safety: The only Gr ≥ 3 AE in ≥ 10% of pts was neutropenia (10%). AEs (all grades, all causality) in > 20% of pts were limited to diarrhea (34%), fatigue (31%), nausea (29%), and cough (26%). All diarrhea events Gr1/2, except one Gr3 event occurring in a pt in Cyc 1, which persisted for 2 days and resolved without dose interruption. Notably, in contrast to similar agents, no drug-related hepatotoxicity or colitis has been observed to date (ave time on study 7 Cyc). 2 episodes of Gr3 fatigue at 1800 mg of a new micronized formulation met the criteria for DLT. Expansion cohorts are open at 800 mg (CLL) and 1200 mg (NHL). Efficacy: A strong exposure-response relationship has been observed. Of 14 evaluable CLL pts, 13 (93%) achieved a nodal PR (median nodal ↓ of 76%), of which 7 (50%) achieved a PR per Hallek 2008 criteria. Responses have been limited in pts with aggressive lymphoma and HL. Of the 12 evaluable FL pts, 8 (67%) remain on study progression-free (range 7 - 99+ weeks), with 3 achieving a PR, notably being the 3 pts exhibiting the highest TGR-1202 plasma concentrations. Conclusions: TGR-1202 is well tolerated in pts with rel/ref heme malignancies with no reported hepatotoxicity or colitis (41% of pts on study 6+ Cyc) and promising activity in CLL and NHL. Enrollment continues in expansion cohorts. Clinical trial information: 01767766.
Trends in use of PET imaging in surveillance of lung and colorectal cancer.
Authors: Christine Marie Veenstra, Anil Vachani, Andrew J Epstein, Christine Agnes Ciunci, Hanna M Zafar, Emily C. Paulson
Journal: Journal of Clinical Oncology (2015)

6563 Background: Surveillance PET imaging following curative intent treatment of non-small cell lung cancer (NSCLC) or colorectal cancer (CRC) is not supported by available evidence. ASCO and ABIM's joint Choosing Wisely campaign recommends against surveillance PET, yet the frequency with which PET imaging is performed during surveillance care is unknown. Methods: 65,748 patients age 66+, diagnosed with stage I-IIIA NSCLC or Stage I-III CRC in 2001-2009, who underwent surgical resection were identified in SEER-Medicare data. Eligibility for surveillance started 180 days post-operatively. Use of imaging was assessed during the first year of surveillance and classified as 1) Any PET: receipt of PET or PET/CT regardless of other imaging, or 2) PET-only: receipt of PET or integrated PET/CT only, in patients who did not undergo separate dedicated CT imaging. Unadjusted proportions of patients receiving each category of surveillance were calculated by cancer type, diagnosis year, and stage. Equality of proportions was assessed between diagnosis years with ANOVA tests. Results: 7,393 NSCLC patients and 35,050 CRC patients met inclusion criteria. PET use more than doubled over the study period in both cohorts. 11% of all NSCLC patients diagnosed in 2001 received any PET vs. 25% diagnosed in 2009 (P < 0.001). Similarly, 4% of all CRC patients diagnosed in 2001 received any PET vs. 12% diagnosed in 2009 (P < 0.001). PET utilization was more common in higher stage NSCLC and CRC patients, and increased significantly between 2001 and 2009. In Stage IIIA NSCLC patients diagnosed in 2001, 15% received any PET compared to 42% diagnosed in 2009 (P = 0.015). In this same group of patients, 1.5% diagnosed in 2001 received PET-only, compared to 15% diagnosed in 2009. Among Stage III CRC patients any PET use increased from 9% for those diagnosed in 2001 to 27% for those diagnosed in 2009 (P < 0.001), while use of PET-only increased from 1% to 8% over the same period (P < 0.001). Conclusions: Although not indicated in surveillance, PET utilization has more than doubled among NSCLC and CRC survivors over the study period. While surveillance rates may be increasing generally, increased rates of PET-only imaging suggest PET is inappropriately replacing existing surveillance protocols.
Identifying biomarkers specific to bone metastases in castrate-resistant prostate cancer.
Authors: Maahum Ali Haider, Colm Morrissey, Ilsa Coleman, Xiaotun Zhang, Lisha Brown, Lori Kollath, Shahriar Koochekpour, Paul H. Lange, Celestia Higano, Peter Nelson, Daniel W. Lin, Robert Vessella, Kristopher Attwood, Mogjan Shourideh, Robert B. Montgomery, Lawrence D. True, Martine Roudier
Journal: Journal of Clinical Oncology (2014)

5092 Background: Castrate-resistant prostate cancer (CRPC) has a propensity to metastasize to bone. There is evidence to suggest a differential response to treatment in bone versus visceral metastases. We sought to identify molecular targets specific to CRPC bone metastases. Methods: Liver (n=19), lymph node (n=68), and bone metastases (n=20) from 54 CRPC patients were laser capture microdissected to identify biomarkers using Agilent Expression Arrays. Tissue microarrays (TMAs) were used to validate the differential expression of proteins of interest in bone (n=117) and visceral (n=65) metastases. Prosaposin (PSAP) was evaluated in serial serum samples from men who presented with localized, recurrent, and metastatic disease. Results: Gene Set Enrichment and Ingenuity Pathway Analyses identified pathways that were altered between bone and visceral metastases (q<0.05): 1) Epithelial mesenchymal transition (ZEB1/2, SNAI1/2, TGFB1, VIM), 2) Survival (BAD, BAX), 3) Innate immune response (CNN2, COL4A1, CCL14, FPR1, TLR4, MMP9, SERPINF1) and 4) Osteomimetic (POSTN, SPP1, RUNX2, DKK1, DMP1, IBSP, THBS3). Based on TMAs, both nuclear and cytoplasmic Twist were higher in bone than in visceral metastases (p<0.01). Nuclear Twist and SLUG were associated with fibroblast-like epithelial cells, suggesting that a subset of nuclear-Twist positive CRPC cells in the bone have high metastatic potential. BCL-2 and MCL-1 survival proteins have been shown to be decreased in CRPC bone metastases. Here we show that BAX and BAD are overexpressed. Moreover, we validated the increased expression of osteomimetic proteins and determined that serum PSAP (which has been associated with disease progression) is elevated in patients who developed bone metastases. Conclusions: Heterogeneity of CRPC metastases both within and between patients is an obstacle in determining the appropriate treatment regimen for each patient. However, our data highlight that differential response to therapy could also be based on the site of metastasis. We have identified biomarkers that differentiate bone from visceral metastases that may represent new therapeutic targets for CRPC bone metastases.
Study of the usefulness of angiotensin type 1 receptor (AGTR1) as a possible response predictor in patients with metastatic breast cancer (mBC) subjected to chemotherapy and treatment with bevacizumab (AVALUZ Study).
Authors: Juan De la Haba- Rodriguez, Javier Salvador Bofill, Manuel Codes, Eva M. Ciruelos, Ana Jaen, Antonio Galan, Miquel Gil, M. Jose Serrano, Jose Manuel Baena, Maria Jose Villanueva Silva, Encarnacion Gonzalez, Adolfo Murias, Ana Miguel, Helena Garcia, Juan L. Bayo, Pedro Sánchez-Rovira
Journal: Journal of Clinical Oncology (2012)

10608 Background: Angiotensin type 1 receptor (AGTR1) is a membrane receptor implicated in the regulation of arterial pressure. It has also been related to carcinogenesis and tumor spread, and participates in neoangiogenesis. AGTR1 is expressed in a number of neoplasms as BC. In a previous neoadjuvant study, a significant relationship was observed between AGTR1 expression and CR to a regimen of chemo and bevacizumab (B). To study and confirm the relationship between tumor expression of AGTR1 and response to a regimen of chemo and B in pts with mBC. Methods: AGTR1 expression was subjected to immunofluorescence (monoclonal AGTR1 sc1173 antibody, Santa Cruz Biotechnology, CA, USA Dilution 1:50) in 50 samples of mBC pts from the AVALUZ study treated with first line bevacizumab 10 mg/kg, paclitaxel 150 mg/m2 and gemcitabine 2000 mg/m2 d 1 and 15 c/28 d until PD, unacceptable toxicity or medical decision. Immunoreactivity was reported as negative (0), low positive (1+) and high positive (2+). RNA was extracted from paraffin blocks, using the QIAamp DNA FFPE Tissue Kit and Deparaffinization Solution (QIAGEN) and expression of AGTR1 candidate gene was quantified using reverse transcription-PCR (RT-PCR). Results: 60% of the samples expressed AGTR1 (26% weak and 34% intense) – expression being more frequent in HR + tumors (65% vs 45%). Among the 50 samples analyzed, measurable disease was present in 39 pts. Treatment activity was significantly greater in the tumors AGTR1 expression 2+ (p=0.009) (Table). With a median follow-up of 19.30 months, the progression-free interval was longer in the tumors with intense AGTR1 expression (17.7 vs 10.8 months, p=0.132). More consolidated PFS and OS will be presented. Conclusions: AGTR1 expression may be useful as a predictor of response to chemo and bevacizumab. Prospective studies are needed to confirm these findings. [Table: see text]
The impact of SPARC expression in survival of pancreatic ductal adenocarcinoma patients after curative resection.
Authors: Masaaki Murakawa, Toru Aoyama, Yohei Miyagi, Yousuke Atsumi, Keisuke Kazama, Satoshi Kobayashi, Makoto Ueno, Manabu Morimoto, Naoto Yamamoto, Tsutomu Sato, Takaki Yoshikawa, Yasushi Rino, Munetaka Masuda, Soichiro Morinaga
Journal: Journal of Clinical Oncology (2017)

321 Background: The predictive roles of secreted protein acidic and rich in cysteine (SPARC) in resected pancreatic ductal adenocarcinoma (PDAC) patients have not been clarified. We investigated the correlations between the SPARC expression and the postoperative prognosis. Methods: We retrospectively analyzed the clinical data from consecutive patients who underwent curative resection for pancreatic cancer in our institution from 2005 to 2014. Stromal SPARC expression was analyzed by immunohistochemistry on tumor tissue microarrays (TMAs) from the patients. Results: 179 patients were enrolled to this study. The median follow-up period of the present study was 62.1 months. 70 patients had positive SPARC expression (39.1%). There were no significant difference between the positive SPARC expression group and negative group. In survival analysis, there was significant difference in the 5-year overall survival (OS) rates after surgery, which were 8.1% and 19.8% between the SPARC positive and negative groups, respectively (p = 0.0316). Univariate analysis showed SPARC expression, size of tumor, lymph node metastasis, and residual tumor as the possible prognostic factors. Multivariate analysis revealed SPARC expression (hazard ratio (HR) = 1.44 95%CI; 1.017-2.051), lymph node metastasis (HR = 2.019 95%CI; 1.318-3.091), and residual tumor (HR = 1.648 95%CI; 1.132-2.401)as the independent prognostic factor. Conclusions: Stromal SPARC expression in resectable pancreatic cancer patients might be useful as the predictive survival marker. The prognostic value of SPARC expression should be confirmed in another cohort or in a prospective multicenter-study.