tbuckley/cabot-search huggingface dataset:
A comprehensive analysis of potentially targetable genetic aberrations and clinical findings in 821 patients with squamous-cell NSCLC – a comparison of NGM and TCGA LUSC data
Authors: S. Koleczko, C. Schäpers, M. Scheffler, M. Ihle, A. Kostenko, S. Michels, R. Fischer, L. Nogova, V. Brandes, D. Abdulla, F. Ueckeroth, M. Thurat, R. Frank, A. Eisert, E. Bitter, C. Wömpner, L. Gogl, S. Merkelbach-Bruse, R. Büttner, J. Wolf
Journal: Annals of Oncology (2016)
Stromal and antitumor effects of BIBF 1120 (nintedanib) in a preclinical lung cancer model.
Authors: David E. Gerber, Bercin Kutluk Cenik, Katherine T Ostapoff, Rolf A. Brekken
Journal: Journal of Clinical Oncology (2012)

e13563 Background: BIBF 1120 is an angiogenic receptor tyrosine kinase inhibitor that potently inhibits VEGFR, PDGFR and FGFR kinase activity in in vitro enzymatic assays. This study investigated the effect and mechanism of BIBF 1120, in vitro and in vivo, as a single agent and in combination with chemotherapy in preclinical models of lung cancer. Methods: Anti-tumor effects of BIBF 1120 in vitro were assessed using cell proliferation assays on five lung cancer lines (A549, Calu-3, Calu-6, H1993, H1703) with BIBF 1120 as a single agent and in combination with gemcitabine and cisplatin. To demonstrate anti-tumor activity in vivo, NOD/SCID mice bearing subcutaneous A549 grafts were treated daily with BIBF 1120 or BIBF 1120 plus chemotherapy. Perfusion studies were conducted using labeled dextrans. Ex vivo tumor tissues were assessed for architecture, microvessel density, pericyte coverage, proliferation, and apoptosis. Results: In vitro, BIBF 1120 did not show anti-proliferative effects at pharmacologically achievable concentrations (IC 50 &gt;20μM) as a single agent; nor did it sensitize tumor cells to chemotherapy. However, BIBF 1120 inhibited primary tumor growth as a single agent and in combination therapy in subcutaneous endpoint studies with A549 xenografts. There was no significant difference in tumor architecture between BIBF 1120 and control-treated animals. Microvessel density (CD31,endomucin) and pericyte-covered vessels (NG2) were significantly decreased in BIBF 1120-treated animals compared to the control and chemotherapy only groups. Proliferation (phospho-histone 3) was decreased and apoptosis (cleaved caspase 3) was increased in BIBF 1120-treated animals compared to the control and chemotherapy only groups. Finally, BIBF 1120 significantly decreased perfusion in A549 xenografts. Conclusions: BIBF 1120 demonstrated potent anti-tumor and anti-angiogenic activity in a preclinical model of lung cancer. Because A549 was previously demonstrated to be an anti-VEGFR therapy resistant cell line, this study highlights the importance of FGFR and PDGFR pathways in the treatment of lung cancer.
A feasibility study of a new smartphone application for patients with cancer.
Authors: Atsuko Kitano, Chikako Shimizu, Yosuke Uchitomi, Narikazu Boku, Jun Ohi, Noriko Sawai, Yoshie Tokonabe, Takashi Fujitomo, Yuta Matsuda, Naomi Sakurai, Yasuhiro Fujiwara
Journal: Journal of Clinical Oncology (2017)

211 Background: Smartphone-applications have been used for self-care, but not all applications have a sufficient level of efficacy. We evaluated the feasibility of a new smartphone application (the App) which has two main functions—diary function and SNS function—and investigated the characteristics of active users. Methods: Patients who visited the Breast and Medical Oncology or GI Medical Oncology divisions at National Cancer Center Hospital were recruited between March and April in 2016. Participants could use the App for 28 days. Web-based survey was performed before and 28 days after using the App. The primary endpoint was Daily Active User (DAU) rate (the number of daily log-in user divided by the number of patients who completed installation). A mean DAU rate higher than 20% was predetermined as feasible. The secondary endpoints were daily diary function user rate, daily SNS function user rate, and overall user rate and change of Edmonton Symptom Assessment System Revised Japanese version (ESAS-r-j) before and after the App use. “Active user” was defined as a participant who used the AppeWe more than median active days for diary or SNS function. Duration of App use was counted from the date of installation to the date of last use, and overall user rate was calculated by Kaplan Meier method. Results: One-hundred and four patients (96%) completed the App installation and answered the first survey. All patients were followed for 28 days. The mean DAU rate was 50.9%. Active diary function user rate was 53% and active SNS function user rate was 40%. Overall user rate was 87.5%. Diary function was used more frequently by male patients than female, and non-breast cancer patients. SNS function was used more frequently by unemployed patients than others, and by patients younger than 40 y/o. We could evaluate the change of ESAS-r-j score in 80 patients who answered the second survey. There was a significant improvement of depression score among patients who were single and who had metastatic disease. Conclusions: The App was considered feasible. Gender, cancer type, job status, and age may influence the behavior of the App use. The App may improve patients’ psychological symptoms, but further investigations are warranted to reveal the clinical utility of the App.
German Adjuvant Intergroup Node Positive (GAIN) study: A phase III trial to compare IDD-ETC versus EC-TX in patients with node-positive primary breast cancer—Final efficacy analysis.
Authors: Volker Jochen Moebus, Gunter Von Minckwitz, Christian Jackisch, Hans-Joachim Lueck, Andreas Schneeweiss, Hans Tesch, Dirk Elling, Nadia Harbeck, Bettina Conrad, Tanja Fehm, Jens Bodo Huober, Volkmar Müller, Ingo Bauerfeind, Marcus Schmidt, Sibylle Loibl, Valentina Nekljudova, Michael Untch, Christoph Thomssen
Journal: Journal of Clinical Oncology (2014)

1009 Background: Intense dose-dense (idd) epirubicin (E), paclitaxel (T), cyclophosphamide (C) (idd-ETC) resulted in a superior disease-free (DFS) and overall survival (OS) compared to conventionally dosed EC-T (q3w) chemotherapy in primary breast cancer patients (pts) with ≥4 involved lymph nodes (LN) (Möbus et al, JCO 2010). The GAIN trial had a 2x2 factorial design for investigating two different dose-dense chemotherapy regimens as well as the use of adjuvant ibandronate treatment. Ibandronate results have been reported previously (von Minckwitz et al, JCO 2013). Here we report the final results of the chemotherapy comparison. Methods: Pts were randomized to idd-ETC (E:150 mg/m², T:225 mg/m², C:2500-2000 mg/m², i.v. day 1, q15 for 3 cycles each) or EC followed by T plus capecitabine (X) (EC-TX) (E: 112.5 mg/m² + C: 600 mg/m², i.v. day 1, q 15 for 4 cycles followed by T: 67.5 mg/m² i.v. day 1, q 8 for 10 weeks + X: 2000 mg/m² p.o. day 1-14, q 22 for 4 cycles). After recruitment of 1,500 patients the dose of C was reduced to 2000 mg/m². Pts aged 18-65 years with involved axillary LN were eligible. 3000 pts with 801 events were needed to show an increase of 5-year DFS (primary endpoint) from 75% to 79% for patients receiving EC→TX after 8 years total study duration. Results: 3,023 patients were randomized from 06/2004 until 08/2008. Median age was 50 years; pN1 (37.7%), pN2 (35.4%), pN3 (26.9%); 46.6% were grade 3. With a median follow up of 74 months we observed 644 DFS events (327 with idd-ETC; 317 with EC-TX) (HR 0.94; log-rank p=0.47). 5-year DFS was 80% with idd-ETC and 82% with EC-TX. No different treatment effect was observed in predefined subgroups. 383 pts have died (205 with idd-ETC; 178 with EC-TX) (HR 0.85; log-rank p=0.10). Hematological toxicity was higher in the idd-ETC arm, but 3 and 11 treatment related deaths occurred in the idd-ETC and EC-TX arm, respectively. Conclusions: Both dose-dense regimens achieved a highly favorable 5-year DFS superior to our assumptions mainly based on the preceeding idd-ETC study. The addition of a fourth cytostatic drug (here capecitabine) did not improve efficacy of dose-dense therapy, but led to higher toxicity. Clinical trial information: NCT 001 968 72.
A functional mammalian target of rapamycin complex 1 signaling is indispensable for c‐Myc‐driven hepatocarcinogenesis
Authors: Pin Liu, Mengmeng Ge, Junjie Hu, Xiaolei Li, Li Che, Kun Sun, Lili Cheng, Yuedong Huang, Maria G. Pilo, Antonio Cigliano, Giovanni M. Pes, Rosa M. Pascale, Stefania Brozzetti, Gianpaolo Vidili, Alberto Porcu, Antonio Cossu, Giuseppe Palmieri, Maria C. Sini, Silvia Ribback, Frank Dombrowski, Junyan Tao, Diego F. Calvisi, Ligong Chen, Xin Chen
Journal: Hepatology (2017)

Amplification and/or activation of the c‐Myc proto‐oncogene is one of the leading genetic events along hepatocarcinogenesis. The oncogenic potential of c‐Myc has been proven experimentally by the finding that its overexpression in the mouse liver triggers tumor formation. However, the molecular mechanism whereby c‐Myc exerts its oncogenic activity in the liver remains poorly understood. Here, we demonstrate that the mammalian target of rapamycin complex 1 (mTORC1) cascade is activated and necessary for c‐Myc‐dependent hepatocarcinogenesis. Specifically, we found that ablation of Raptor , the unique member of mTORC1, strongly inhibits c‐Myc liver tumor formation. Also, the p70 ribosomal S6 kinase/ribosomal protein S6 and eukaryotic translation initiation factor 4E‐binding protein 1/eukaryotic translation initiation factor 4E signaling cascades downstream of mTORC1 are required for c‐Myc‐driven tumorigenesis. Intriguingly, microarray expression analysis revealed up‐regulation of multiple amino acid transporters, including solute carrier family 1 member A5 (SLC1A5) and SLC7A6, leading to robust uptake of amino acids, including glutamine, into c‐Myc tumor cells. Subsequent functional studies showed that amino acids are critical for activation of mTORC1 as their inhibition suppressed mTORC1 in c‐Myc tumor cells. In human hepatocellular carcinoma specimens, levels of c‐Myc directly correlate with those of mTORC1 activation as well as of SLC1A5 and SLC7A6. Conclusion : Our current study indicates that an intact mTORC1 axis is required for c‐Myc‐driven hepatocarcinogenesis; thus, targeting the mTOR pathway or amino acid transporters may be an effective and novel therapeutic option for the treatment of hepatocellular carcinoma with activated c‐Myc signaling. (H epatology 2017;66:167–181).
Preventing Dementia
Authors: Steven T. DeKosky, Lon S. Schneider
Journal: JAMA Neurology (2017)

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Falls and fractures during aromatase inhibitors (AI) therapy.
Authors: Margaret Emily Williams, Palak Choksi, Kelley M Kidwell, Julia Stella, David A Hanauer, Catherine H. Van Poznak
Journal: Journal of Clinical Oncology (2015)

e20635 Background: AI therapy may promote loss of bone mineral density and fractures. We investigated the incidence of falls and fractures in patients (pts) on adjuvant (adj) AI compared to aged-matched controls without BCA and without AI exposure. Methods: Using the University of Michigan (UM) Health System Electronic Medical Records Search Engine (EMERSE) and the UM Cancer Registry an IRB approved retrospective review was performed. Women with HR+ BCA on adj AI were identified (case) and matched to controls based on age and race. Fall and fracture data were abstracted from the medical record from the time of initiating AI to 3 months after stopping AI and for controls. Results: 332 pairs of women were matched on age and race. In 59 pairs (17.8%) the control fell but the case did not. In 61 pairs (18.4%) the case fell but the control did not. There was no statistically significant difference in the rate of falls in age-matched cases and controls, p = 0.86 using conditional logistic regression. For pairs in which control fell but case did not, median age at fall was 67, compared with median age of 64 for pairs in which case fell but control did not, p = 0.17. For pairs where both pts fell (n = 22), there was no difference in the age of pts at time of fall, p = 0.19 using sign test. The rate of fractures between cases and controls was not statistically different, p = 1.0 using conditional logistic regression. There were 35 pairs (10.5%) in which case fractured and control did not and 35 pairs (10.5%) where the control fractured and case did not. There was low power to detect difference in age at time of fracture as there were only 6 pairs in which both pts had fractures, thus we find no significant difference in the age at fracture between cases and controls. p = 0.22 (sign test). For pairs in which control fractured but case did not, mean age at fracture was 71 as compared with 61 for pairs in which case fractured but control did not, p = 0.0003. Conclusions: This study did not identify a difference in falls or fractures in women on AIs compared to their age matched controls. The sample size and the retrospective nature of the study design may have limited our ability to identify a difference between groups. To better define the risk of fall and fracture in pts receiving adj AI, a prospective study would be warranted.
Clinical Images: Chronic Nonbacterial Osteomyelitis
Authors: Yusuke Takeuchi, Kosaku Murakami, Nobuo Kuramoto, Ran Nakashima, Motomu Hashimoto, Yoshitaka Imura, Hajime Yoshifuji, Koichiro Ohmura, Tsuneyo Mimori
Journal: Arthritis & Rheumatology (2017)
Block copolymer-boron cluster conjugate for effective boron neutron capture therapy of solid tumors
Authors: Peng Mi, Hironobu Yanagie, Novriana Dewi, Hung-Chi Yen, Xueying Liu, Minoru Suzuki, Yoshinori Sakurai, Koji Ono, Hiroyuki Takahashi, Horacio Cabral, Kazunori Kataoka, Nobuhiro Nishiyama
Journal: Journal of Controlled Release (2017)
Impact of concomitant bone-targeted therapies (BTT) on outcomes in metastatic castration-resistant prostate cancer (mCRPC) patients (pts) without prior chemotherapy (ctx) treated with abiraterone acetate (AA) or prednisone (P).
Authors: Fred Saad, Karim Fizazi, Matthew R. Smith, Thomas W. Griffin, Anil Londhe, Dana E. Rathkopf, Arturo Molina, Charles J. Ryan
Journal: Journal of Clinical Oncology (2013)

5037 Background: BTT can delay symptomatic progression in cancer pts with bone metastases. In a post hoc analysis, we assessed the impact of concomitant BTT on outcomes in a recent large, multinational study in mCRPC pts without prior ctx. Methods: COU-AA-302 was a phase III trial in asymptomatic/mildly symptomatic pts with progressive mCRPC and no prior ctx. 1,088 pts were stratified by ECOG performance status (ECOG-PS, 0 vs 1) and randomized 1:1 to AA 1 g or placebo QD, plus prednisone 5 mg BID. Radiographic progression-free survival (rPFS) and overall survival (OS) were primary end points; secondary end points were times to opiate use, ctx, ECOG-PS deterioration, and PSA progression. The effect of concomitant use of BTT on all end points was assessed retrospectively using a stratified Cox regression model with factors for treatment, concomitant BTT, interaction of treatment and BTT, and baseline covariates. All data were obtained from a prespecified interim analysis at 55% OS events. Results: Median follow-up at the time of analysis was 27.1 mos. Among intent-to-treat (ITT) pts, 184/546 AA and 169/542 P pts received concomitant BTT for treatment of bone metastases, either zoledronic acid (n = 330), other bisphosphonates (n = 16), denosumab (n = 22), and/or other BTT (n = 5). In these pts, concomitant BTT use was associated with improved OS, time to opiate use for cancer pain, and time to ECOG-PS deterioration (Table). Results were similar in a sensitivity analysis including only ITT pts with bone metastases at baseline. Conclusions: In this post hoc, exploratory analysis, concomitant BTT use was associated with delayed symptomatic progression in asymptomatic/mildly symptomatic mCRPC pts. This potential clinical benefit should be investigated in prospective studies. Clinical trial information: NCT00887198. [Table: see text]
Predictors of clinical metastases and survival among nonmetastatic prostate cancer (PC) patients (pts) treated with androgen-deprivation therapy (ADT) in Sweden.
Authors: Rohini Khorana Hernandez, Johan Mesterton, Jonas Banefelt, Jan Stålhammar, Patrik Sobocki, Bo-Eric Persson, Alexander Liede
Journal: Journal of Clinical Oncology (2013)

e16066 Background: ADT is the standard of care in Sweden for PC pts with signs of recurrence after primary therapy (tx). Studies of predictors of metastasis (mets) and survival have largely focused on pt characteristics at cancer diagnosis. Time-varying factors, such as prostate-specific antigen (PSA) levels, may have greater impact on a pt’s risk of disease progression. This study examines predictors of mets and survival among men with PC treated with ADT. Methods: Using electronic medical records from Swedish urology clinics linked to national registries (Cancer Registry, National Pt Registry, Cause of Death Registry), we identified men with PC and no evidence of mets treated with ≥6 months (mos) ADT (gonadotropin-releasing hormone agonists/antagonists or bilateral orchiectomy) between 2000-2010 with ≥2 PSA values. Men were followed from ADT index date to mets, death, or end of follow-up (12/31/2010). Multivariate competing risks regression analysis was used to estimate hazard ratios (HR) and 95% CIs; predictors and covariates of interest included PC diagnosis year (yr), age, comorbidities, anti-androgen tx, region, and time-varying characteristics (PSA absolute value, PSA doubling time [DT]). Results: Cohort was 446 men with mean follow-up of 3.3 yrs. Most mets were to the bone (7-yr cumulative incidence 25% for bone, 30% for any mets). Median survival was 6 yrs (5.9 mos after bone mets, 6.1 mos after any mets). Higher PSA and shorter PSA DT were strong predictors of all outcomes. In particular, PSA DT ≤ 6 mos was associated with increased risk of bone mets (13.9 [8.0 – 24.1]), any mets (7.9 [4.9 – 12.8]), mortality (5.7 [3.9 – 8.5]), and bone mets-free survival (6.9 [4.7–10.1]) when compared to PSA DT &gt; 6 mos. HRs were adjusted for age, Charlson comorbidity index, anti-androgen tx, and region. Conclusions: PC pts treated with ADT are at significant risk of bone mets, any mets, and death. This study based on real-world data demonstrates the importance of PSA measured after ADT initiation in defining high risk of these outcomes, particularly PSA DT ≤6 mos. PC pts may benefit from new tx to prevent disease progression since survival is short after bone or other mets.
Meta-analysis examining impact of age on pemetrexed (pem) efficacy for the treatment of advanced nonsquamous (NS) non-small cell lung cancer (NSCLC).
Authors: Luis Paz-Ares, Annamaria Zimmermann, Tudor-Eliade Ciuleanu, Paul A. Bunn, Belen San Antonio, Jonathan Denne, Nancy Iturria, William J. John, Giorgio Vittorio Scagliotti
Journal: Journal of Clinical Oncology (2014)

e19040 Background: Elderly patients (pts) are often undertreated relative to younger pts in clinical practice. Pem is efficacious as a first-line, second-line, and maintenance treatment for advanced NS NSCLC. Analysis of individual trials in first-line (JMDB) and maintenance (JMEN, PARAMOUNT) settings showed comparable survival (favoring pem over comparators) and toxicity profiles of pem in elderly and nonelderly subgroups. Now, a meta-analysis is presented to give an integrated review of the impact of age on pem efficacy. Methods: Data from NS NSCLC pts participating in four pem phase III studies underwent meta-analysis using a random-effects model that includes a statistical parameter representing inter-study variation including population size and event number. The method of DerSimonian and Laird was used to estimate the inter-study treatment effect variance. Studies included in the meta-analysis were: JMEI (second-line pem, N=399); JMDB (first-line pem/cisplatin, N=1,252); JMEN (pem maintenance after non-pem/platinum doublet, N=481); and PARAMOUNT (pem maintenance after first-line pem/cisplatin, N=539). Pts in all studies were ECOG performance status (PS) 0/1, except JMEI had 11-12% PS 2 pts. Due to differences in treatment regimens across studies, the ratio of the overall survival (OS) hazard ratio (HR) (pem versus control) for younger pts over the OS HR for older pts within each study was used as the measure of the differential effect of pem. Data were examined using age cutoffs of 65 and 70. Results: Among the four studies, 32% of the pts were age ≥65, and 14% were age ≥70. The test of heterogeneity among studies was non-significant for subgroups defined by age 65 (P=0.083) and age 70 (P=0.848). The pooled ratio of the OS HR (pem versus control) in pts <65 to that in pts ≥65 was estimated as 0.92 (95% CI 0.67-1.25). Similar results were seen for the analysis using the age 70 cutoff, with a pooled ratio of 0.80 (95% CI 0.62-1.04). Conclusions: In an analysis including 2,671 good PS NS NSCLC pts, the effect of pem on OS was similar in younger and older pts as evidenced by the pooled HR ratio close to 1. Pem is an efficacious treatment for advanced NS NSCLC regardless of pt age. Clinical trial information: NCT00789373.